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Clinical Trial Results:
A phase III/IV, cluster-randomized, controlled study to evaluate the effectiveness of GlaxoSmithKline Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in reducing the incidence of invasive diseases.

Summary
EudraCT number	2008-005149-48
Trial protocol	FI
Global end of trial date	05 Oct 2013

Results information
Results version number	v4(current)
This version publication date	02 Jan 2021
First version publication date	29 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

111442

ISRCTN number

US NCT number

NCT00861380

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

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

Public contact

Clinical Disclosure Advisor,, GlaxoSmithKline Biologicals,, 044 2089904466, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline Biologicals, 044 2089904466, 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

15 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Oct 2013

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%.

Protection of trial subjects

The nurses administering vaccines were instructed to observe the vaccinees 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. In addition, an Independent Data Monitoring Committee (IDMC) was set up, of which responsibilities 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 safety results; (3) Recommendations for stopping the trial for effectiveness or safety reasons when appropriate.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 May 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 87165

Worldwide total number of subjects

87165

EEA total number of subjects

87165

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)

87165

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 also served as basis for conducting a long-term evaluation of the impact of vaccination with GSK Biologicals’ 10Pn-PD-DiT vaccine. Subjects of the 10PN-PD-DIT-053 (112595) study (NCT00839254-EUDRACT:2008-006551-51) contributed to the objectives of this study.

Screening details

41188 subjects were enrolled in the study, 7 subjects didn't receive any vaccination, 41181 subjects started the study. Total population assessed for combined analyses performed on both studies included 45977 subjects, see details in groups description.

Number of subjects started

87165

Number of subjects completed

41181

Reason: Number of subjects

10PN-043 Subjects not vaccinated: 7

Reason: Number of subjects

10PN043-053 subjects: 45977

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

Are arms mutually exclusive

Yes

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

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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.

Ctrl-6W-6M/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (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). 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/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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) (11-17M 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/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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) (11-17M 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/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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/043 Group

Arm description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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/043 Group	10Pn2+1-6W-6M/043 Group	Ctrl-6W-6M/043 Group	10Pn7-11M/043 Group	Ctrl7-11M/043 Group	10Pn12-18M/043 Group	Ctrl12-18M/043 Group
Started	8427	9112	8872	3689	1812	6249	3020
Completed	0	0	0	0	0	0	0
Not completed	8427	9112	8872	3689	1812	6249	3020
Withdrawal Information not recorded	8427	9112	8872	3689	1812	6249	3020

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Subjects from the 10PN-PD-DIT-053 (112595) study (NCT00839254-EUDRACT:2008-006551-51) contributed to objectives of this study i.e.: a total of 45977 subjects were part of objective analysis for both studies. 41188 subjects were enrolled in the study. 41181 of these were actually vaccinated and included in baseline period of the study.

Baseline characteristics

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Reporting group title

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

Reporting group description

Reporting group title

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

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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

Ctrl-6W-6M/043 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (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). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn7-11M/043 Group

Reporting group description

Reporting group title

Ctrl7-11M/043 Group

Reporting group description

Reporting group title

10Pn12-18M/043 Group

Reporting group description

Reporting group title

Ctrl12-18M/043 Group

Reporting group description

Reporting group values	10Pn3+1-6W-6M/043 Group	10Pn2+1-6W-6M/043 Group	Ctrl-6W-6M/043 Group	10Pn7-11M/043 Group	Ctrl7-11M/043 Group	10Pn12-18M/043 Group	Ctrl12-18M/043 Group	Total
Number of subjects	8427	9112	8872	3689	1812	6249	3020	41181
Age Categorical
Units: Participants
28 days - 23 months	8427	9112	8872	3689	1812	6249	3020	41181
Sex: Female, Male
Units: Participants
Female	4239	4399	4351	0	0	0	0	12989
Male	4188	4713	4521	0	0	0	0	13422
Unknown	0	0	0	3689	1812	6249	3020	14770

End points

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Reporting group title

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

Reporting group description

Reporting group title

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

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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

Ctrl-6W-6M/043 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (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). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn7-11M/043 Group

Reporting group description

Reporting group title

Ctrl7-11M/043 Group

Reporting group description

Reporting group title

10Pn12-18M/043 Group

Reporting group description

Reporting group title

Ctrl12-18M/043 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) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) (i.e. 1846 subjects) studies, pooled, and 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). Refer to group description for 10Pn3+1-6W-6M/043 Group for 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) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) (i.e. 1329 subjects) studies, pooled, and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (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 description for Ctrl6W-6M/043 Group for 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) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) (i.e. 942 subjects) studies, pooled, and 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). Refer to group description for 10Pn2+1-6W-6M/043 Group for 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) and 10PN-PD-DIT-053 (NCT00839254 - EUDRACT 2008-006551-51) (i.e. 191 subjects) studies, pooled, and 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) (11-17M Schedule). Refer to group description for 10Pn7-11M/043 Group for 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

Subject analysis set title

10Pn12-18M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Ctrl12-18M/043+053 Group

Subject analysis set type

Per protocol

Subject analysis set description

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

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

Number of subjects included in analysis

20474

Analysis specification

Pre-specified

Analysis type

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

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

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

^[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+1vsControl). 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 (till end of blinded ID FU period)

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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 (till end of blinded ID FU period)

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 (till end of blinded ID FU period)

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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 (till end of blinded ID FU period)

End point description

End point type

Secondary

End point timeframe

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

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 (+ indirect effects on the unvaccinated population)

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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 (+ indirect effects on the unvaccinated population)

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 (0.0003 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)

Statistical analysis 1

Statistical analysis description

For indirect effectiveness analysis at preventing Culture-confirmed IPD (any serotype), number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[5]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

14.657

Confidence interval

level

95%

sides

2-sided

lower limit

13.229

upper limit

16.197

Notes
[5] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 2626735.

Statistical analysis 2

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[6]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

13.582

Confidence interval

level

95%

sides

2-sided

lower limit

11.691

upper limit

15.693

Notes
[6] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 1354702.

Statistical analysis 3

Statistical analysis description

For indirect effectiveness analysis at preventing Culture-confirmed IPD (vaccine serotype), number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

8.452

Confidence interval

level

95%

sides

2-sided

lower limit

7.376

upper limit

9.639

Notes
[7] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 2626735.

Statistical analysis 4

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[8]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

7.603

Confidence interval

level

95%

sides

2-sided

lower limit

6.206

upper limit

9.221

Notes
[8] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 1354702.

Statistical analysis 5

Statistical analysis description

For indirect effectiveness analysis at preventing Culture-confirmed IPD (vaccine related), number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[9]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

1.637

Confidence interval

level

95%

sides

2-sided

lower limit

1.185

upper limit

2.205

Notes
[9] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 2626735.

Statistical analysis 6

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[10]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

1.845

Confidence interval

level

95%

sides

2-sided

lower limit

1.194

upper limit

2.724

Notes
[10] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons = 1354702.

Statistical analysis 7

Statistical analysis description

For indirect effectiveness analysis at preventing Culture-confirmed IPD (non-vaccine & non-vaccine related), number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[11]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

3.997

Confidence interval

level

95%

sides

2-sided

lower limit

3.269

upper limit

4.839

Notes
[11] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as . 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons = 2626735.

Statistical analysis 8

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[12]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

3.322

Confidence interval

level

95%

sides

2-sided

lower limit

2.423

upper limit

4.445

Notes
[12] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons = 1354702.

Statistical analysis 9

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[13]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

14.487

Confidence interval

level

95%

sides

2-sided

lower limit

13.071

upper limit

16.015

Notes
[13] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2636783.

Statistical analysis 10

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[14]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

13.74

Confidence interval

level

95%

sides

2-sided

lower limit

11.841

upper limit

15.857

Notes
[14] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1360966.

Statistical analysis 11

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[15]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

7.813

Confidence interval

level

95%

sides

2-sided

lower limit

6.782

upper limit

8.955

Notes
[15] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2636783.

Statistical analysis 12

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[16]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

7.789

Confidence interval

level

95%

sides

2-sided

lower limit

6.377

upper limit

9.42

Notes
[16] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1360966.

Statistical analysis 13

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[17]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

2.313

Confidence interval

level

95%

sides

2-sided

lower limit

1.77

upper limit

2.972

Notes
[17] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2636783.

Statistical analysis 14

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[18]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

1.984

Confidence interval

level

95%

sides

2-sided

lower limit

1.307

upper limit

2.886

Notes
[18] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1360966.

Statistical analysis 15

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[19]

Method

Negative Binomial model without strata

Parameter type

PYAR

Point estimate

4.172

Confidence interval

level

95%

sides

2-sided

lower limit

3.429

upper limit

5.028

Notes
[19] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model without strata). Total number of non-vaccinated persons =2636783.

Statistical analysis 16

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[20]

Method

Negative Binomial model without strata

Parameter type

PYAR

Point estimate

3.968

Confidence interval

level

95%

sides

2-sided

lower limit

2.981

upper limit

5.177

Notes
[20] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model without strata). Total number of non-vaccinated persons =1360966.

Statistical analysis 17

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[21]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

14.017

Confidence interval

level

95%

sides

2-sided

lower limit

12.628

upper limit

15.516

Notes
[21] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2654010.

Statistical analysis 18

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[22]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

15.066

Confidence interval

level

95%

sides

2-sided

lower limit

13.079

upper limit

17.269

Notes
[22] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1367343.

Statistical analysis 19

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[23]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

5.916

Confidence interval

level

95%

sides

2-sided

lower limit

5.026

upper limit

6.917

Notes
[23] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2654010.

Statistical analysis 20

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[24]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

8.557

Confidence interval

level

95%

sides

2-sided

lower limit

7.077

upper limit

10.255

Notes
[24] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1367343.

Statistical analysis 21

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[25]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

2.977

Confidence interval

level

95%

sides

2-sided

lower limit

2.357

upper limit

3.71

Notes
[25] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons =2654010.

Statistical analysis 22

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[26]

Method

Regression, Linear

Parameter type

PYAR

Point estimate

2.048

Confidence interval

level

95%

sides

2-sided

lower limit

1.361

upper limit

2.96

Notes
[26] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata). Total number of non-vaccinated persons =1367343.

Statistical analysis 23

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[27]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

5.011

Confidence interval

level

95%

sides

2-sided

lower limit

4.196

upper limit

5.939

Notes
[27] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2654010.

Statistical analysis 24

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9661

Analysis specification

Pre-specified

Analysis type

^[28]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

4.315

Confidence interval

level

95%

sides

2-sided

lower limit

3.285

upper limit

5.566

Notes
[28] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a culture confirmed IPD divided by sum of follow-up period expressed in years (per 100000), as well as the 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1367343.

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

Top of page

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

Top of page

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

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

Top of page

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 (+ indirect effects on the unvaccinated population)

Top of page

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 (+ indirect effects on the unvaccinated population)

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

Top of page

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

Top of page

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

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

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

Top of page

End point title

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

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=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)	15.572 (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 (+ indirect effects on the unvaccinated population)

Top of page

End point title

Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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=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)

Statistical analysis 1

Statistical analysis description

For indirect effectiveness analysis at preventing Hospital-diagnosed Pneumonia, number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[29]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

9.218

Confidence interval

level

95%

sides

2-sided

lower limit

9.103

upper limit

9.335

Notes
[29] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2626735.

Statistical analysis 2

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[30]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

9.212

Confidence interval

level

95%

sides

2-sided

lower limit

9.052

upper limit

9.375

Notes
[30] - In 5 to 99+ Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1354702.

Statistical analysis 3

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[31]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

10.378

upper limit

10.624

Notes
[31] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2636783.

Statistical analysis 4

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[32]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

10.429

Confidence interval

level

95%

sides

2-sided

lower limit

10.259

upper limit

10.601

Notes
[32] - In 5 to 99+ Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1360966.

Statistical analysis 5

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[33]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

10.118

Confidence interval

level

95%

sides

2-sided

lower limit

9.997

upper limit

10.239

Notes
[33] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =2654010.

Statistical analysis 6

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[34]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

9.921

Confidence interval

level

95%

sides

2-sided

lower limit

9.755

upper limit

10.088

Notes
[34] - In 5 to 99+ Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with a Hospital-diagnosed Pneumonia divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =1367343.

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

Top of page

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

Top of page

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

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

Top of page

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

Top of page

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

Top of page

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

Top of page

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

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

Top of page

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 (+ indirect effects on the unvaccinated population)

Top of page

End point title

Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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)

Statistical analysis 1

Statistical analysis description

For indirect effectiveness analysis at preventing Tympanostomy Tube Placements, number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[35]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

22.624

Confidence interval

level

95%

sides

2-sided

lower limit

22.02

upper limit

23.24

Notes
[35] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =229978.

Statistical analysis 2

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[36]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

22.747

Confidence interval

level

95%

sides

2-sided

lower limit

21.912

upper limit

23.606

Notes
[36] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =120190.

Statistical analysis 3

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[37]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

24.503

Confidence interval

level

95%

sides

2-sided

lower limit

23.852

upper limit

25.166

Notes
[37] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =214181.

Statistical analysis 4

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[38]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

26.236

Confidence interval

level

95%

sides

2-sided

lower limit

25.308

upper limit

27.189

Notes
[38] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =112060.

Statistical analysis 5

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[39]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

27.502

Confidence interval

level

95%

sides

2-sided

lower limit

26.81

upper limit

28.207

Notes
[39] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =211914.

Statistical analysis 6

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[40]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

26.1

Confidence interval

level

95%

sides

2-sided

lower limit

25.171

upper limit

27.055

Notes
[40] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111071.

Statistical analysis 7

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[41]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

28.661

Confidence interval

level

95%

sides

2-sided

lower limit

27.958

upper limit

29.377

Notes
[41] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =213913.

Statistical analysis 8

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[42]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

29.835

Confidence interval

level

95%

sides

2-sided

lower limit

28.843

upper limit

30.85

Notes
[42] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Tympanostomy Tube Placement divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111414.

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

Top of page

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

Top of page

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

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

Top of page

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 (+ indirect effects on the unvaccinated population)

Top of page

End point title

Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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)

Statistical analysis 1

Statistical analysis description

For indirect effectiveness analysis at preventing Antimicrobial Prescriptions, number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[43]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

816.813

Confidence interval

level

95%

sides

2-sided

lower limit

815.226

upper limit

818.392

Notes
[43] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =229978.

Statistical analysis 2

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[44]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

841.176

Confidence interval

level

95%

sides

2-sided

lower limit

839.098

upper limit

843.239

Notes
[44] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =120190.

Statistical analysis 3

Statistical analysis description

For indirect effectiveness analysis at preventing Antimicrobial Prescriptions recommended for Acute Otitis Media (AOM)/Respiratory Tract Infections (RTI), number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any 10PN-PD-DIT vaccine - age stratum schedules).

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[45]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

702.245

Confidence interval

level

95%

sides

2-sided

lower limit

700.372

upper limit

704.114

Notes
[45] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =229978.

Statistical analysis 4

Statistical analysis description

For indirect effectiveness analysis at preventing Antimicrobial Prescriptions recommended for AOM/RTI, number of events in the unvaccinated cohort, which occurred around 6 months or more after study start was compared with treated group numbers (applicable to any control (HAV or HBV) vaccine - age stratum schedules).

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[46]

Method

negative Binomial model with strata

Parameter type

PYAR

Point estimate

720.9

Confidence interval

level

95%

sides

2-sided

lower limit

718.355

upper limit

723.435

Notes
[46] - In 0 to 7 Years Old Population, in Year 2009, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =120190.

Statistical analysis 5

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[47]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

929.844

Confidence interval

level

95%

sides

2-sided

lower limit

928.755

upper limit

930.923

Notes
[47] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =214181.

Statistical analysis 6

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[48]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

953.025

Confidence interval

level

95%

sides

2-sided

lower limit

951.77

upper limit

954.257

Notes
[48] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =112060.

Statistical analysis 7

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[49]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

804.703

Confidence interval

level

95%

sides

2-sided

lower limit

803.017

upper limit

806.38

Notes
[49] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =214181.

Statistical analysis 8

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[50]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

818.66

Confidence interval

level

95%

sides

2-sided

lower limit

816.391

upper limit

820.912

Notes
[50] - In 0 to 7 Years Old Population, in Year 2010, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =112060.

Statistical analysis 9

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[51]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

916.079

Confidence interval

level

95%

sides

2-sided

lower limit

914.891

upper limit

917.256

Notes
[51] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =211914.

Statistical analysis 10

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[52]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

928.568

Confidence interval

level

95%

sides

2-sided

lower limit

927.038

upper limit

930.076

Notes
[52] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111071.

Statistical analysis 11

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[53]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

796.894

Confidence interval

level

95%

sides

2-sided

lower limit

795.175

upper limit

798.605

Notes
[53] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =211914.

Statistical analysis 12

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[54]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

803.918

Confidence interval

level

95%

sides

2-sided

lower limit

801.571

upper limit

806.25

Notes
[54] - In 0 to 7 Years Old Population, in Year 2011, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111071.

Statistical analysis 13

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[55]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

865.679

Confidence interval

level

95%

sides

2-sided

lower limit

864.227

upper limit

867.121

Notes
[55] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =213913.

Statistical analysis 14

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[56]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

871.749

Confidence interval

level

95%

sides

2-sided

lower limit

869.771

upper limit

873.707

Notes
[56] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111414.

Statistical analysis 15

Statistical analysis description

Comparison groups

10Pn12-18M/043+053 Group v Ctrl12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[57]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

753.423

Confidence interval

level

95%

sides

2-sided

lower limit

751.591

upper limit

755.249

Notes
[57] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received 10Pn-PD-DiT vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =213913.

Statistical analysis 16

Statistical analysis description

Comparison groups

Ctrl12-18M/043+053 Group v 10Pn12-18M/043+053 Group

Number of subjects included in analysis

9660

Analysis specification

Pre-specified

Analysis type

^[58]

Method

Negative Binomial model with strata

Parameter type

PYAR

Point estimate

755.542

Confidence interval

level

95%

sides

2-sided

lower limit

753.008

upper limit

758.064

Notes
[58] - In 0 to 7 Years Old Population, in Year 2012, for Non-vaccinated persons living in study cluster areas, in which study participants received control vaccine, PYAR was calculated (= number of subjects reported with recommended Antimicrobial Prescriptions divided by sum of follow-up period expressed in years (per 1000), as well as 95% CI (2-sided profile log-likelihood ratio 95% CI using a Negative Binomial regression model with strata). Total number of non-vaccinated persons =111414.

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

Top of page

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	Ctrl-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group
Number of subjects analysed	0 ^[59]	24	2
Units: Participants
Serotype-4 -Pencillin-S		1	0
Serotype-6A -Pencillin-S		1	0
Serotype-6B -Pencillin-I		3	0
Serotype-6B -Pencillin-R		1	0
Serotype-6B -Pencillin-S		2	0
Serotype-7F -Pencillin-S		1	1
Serotype-14 -Pencillin-I		2	0
Serotype-14 -Pencillin-R		1	0
Serotype-14 -Pencillin-S		2	0
Serotype-15C -Pencillin-S		1	0
Serotype-18C -Pencillin-S		1	0
Serotype-19A -Pencillin-I		1	0
Serotype-19F -Pencillin-I		1	0
Serotype-19F -Pencillin-S		1	0
Serotype-23F -Pencillin-S		1	0
Serotype-N -Pencillin-N		4	1
Serotype-4 -Erythromycin-S		1	0
Serotype-6A -Erythromycin-S		1	0
Serotype-6B -Erythromycin-R		5	0
Serotype-6B -Erythromycin-S		1	0
Serotype-7F -Erythromycin-S		1	1
Serotype-14 -Erythromycin-R		4	0
Serotype-14 -Erythromycin-S		1	0
Serotype-15C -Erythromycin-S		1	0
Serotype-18C -Erythromycin-S		1	0
Serotype-19A -Erythromycin-S		1	0
Serotype-19F -Erythromycin-R		1	0
Serotype-19F -Erythromycin-S		1	0
Serotype-23F -Erythromycin-S		1	0
Serotype-N -Erythromycin-N		4	1
Serotype-4 -Tetracyclin-S		1	0
Serotype-6A -Tetracyclin-S		1	0
Serotype-6B -Tetracyclin-R		4	0
Serotype-6B -Tetracyclin-S		2	0
Serotype-7F -Tetracyclin-S		1	1
Serotype-14 -Tetracyclin-S		5	0
Serotype-15C -Tetracyclin-S		1	0
Serotype-18C -Tetracyclin-S		1	0
Serotype-19A -Tetracyclin-S		1	0
Serotype-19F -Tetracyclin-R		1	0
Serotype-19F -Tetracyclin-S		1	0
Serotype-23F -Tetracyclin-S		1	0
Serotype-N -Tetracyclin-N		4	1
Serotype-4 -Levoffloxacin-S		1	0
Serotype-6A -Levoffloxacin-S		1	0
Serotype-6B -Levoffloxacin-S		6	0
Serotype-7F -Levoffloxacin-S		1	1
Serotype-14 -Levoffloxacin-S		5	0
Serotype-15C -Levoffloxacin-S		1	0
Serotype-18C -Levoffloxacin-S		1	0
Serotype-19A -Levoffloxacin-S		1	0
Serotype-19F -Levoffloxacin-S		2	0
Serotype-23F -Levoffloxacin-S		1	0
Serotype-N -Levoffloxacin-N		4	1
Serotype-4 -Ceftriaxone-S		1	0
Serotype-6A -Ceftriaxone-S		1	0
Serotype-6B -Ceftriaxone-S		6	0
Serotype-7F -Ceftriaxone-S		1	1
Serotype-14 -Ceftriaxone-I		1	0
Serotype-14 -Ceftriaxone-S		4	0
Serotype-15C -Ceftriaxone-S		1	0
Serotype-18C -Ceftriaxone-S		1	0
Serotype-19A -Ceftriaxone-S		1	0
Serotype-19F -Ceftriaxone-S		2	0
Serotype-23F -Ceftriaxone-S		1	0
Serotype-N -Ceftriaxone-N		4	1
Serotype-4 -Clindamycin-S		1	0
Serotype-6A -Clindamycin-S		1	0
Serotype-6B -Clindamycin-R		4	0
Serotype-6B -Clindamycin-S		2	0
Serotype-7F -Clindamycin-S		1	1
Serotype-14 -Clindamycin-N		1	0
Serotype-14 -Clindamycin-S		4	0
Serotype-15C -Clindamycin-S		1	0
Serotype-18C -Clindamycin-S		1	0
Serotype-19A -Clindamycin-S		1	0
Serotype-19F -Clindamycin-R		1	0
Serotype-19F -Clindamycin-S		1	0
Serotype-23F -Clindamycin-S		1	0
Serotype-N -Clindamycin-N		4	1

Notes
[59] - No participants with results in 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	Ctrl-6W-6M/043+053 Group	10Pn2+1-6W-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	171	190	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	Ctrl-6W-6M/043+053 Group	10Pn2+1-6W-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	171	190	31	22	62	48
Units: Participants	158	94	124	14	15	27	19

No statistical analyses for this end point

Secondary: Number of subjects with SAEs reported during the blinded invasive disease phase, of the study

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End point title

Number of subjects with SAEs reported during the blinded invasive disease phase, of the study

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

For Month 0 till the end of the blinded ID Follow-Up, (at least 30 months from study start)

End point values	10Pn3+1-6W-6M/043 Group	10Pn2+1-6W-6M/043 Group	Ctrl-6W-6M/043 Group	10Pn7-11M/043 Group	Ctrl7-11M/043 Group	10Pn12-18M/043 Group	Ctrl12-18M/043 Group
Number of subjects analysed	8427	9112	8872	3689	1812	6249	3020
Units: Participants	6	7	8	3	2	2	2

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 study start) up to the end of 18-month period after study unblinding

End point values	10Pn3+1-6W-6M/043+053 Group	Ctrl-6W-6M/043+053 Group	10Pn2+1-6W-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	10201	10054	3880	1908	6535	3126
Units: Participants	1	0	2	0	0	0	0

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

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

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

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

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	Ctrl-6W-6M/043+053 Group	10Pn2+1-6W-6M/043+053 Group
Number of subjects analysed	10201	10053
Units: Participants per 1000 person-years
number (confidence interval 95%)
Culture confirmed ID	0.268 (0.170 to 0.402)	0.047 (0.013 to 0.122)
Pneumococcal invasive disease (IPD)	0.21 (0.124 to 0.331)	0.024 (0.003 to 0.086)
Vaccine serotypes (vaccine type-IPD)	0.140 (0.072 to 0.244)	0.012 (0.0 to 0.066)
Serotype 4	0.0 (0.0 to 0.043)	0.0 (0.0 to 0.044)
Serotype 6B	0.058 (0.019 to 0.136)	0.0 (0.0 to 0.044)
Serotype 7F	0.0 (0.0 to 0.043)	0.012 (0.0 to 0.066)
Serotype 14	0.047 (0.013 to 0.119)	0.0 (0.0 to 0.044)
Serotype 18C	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)
Serotype 19F	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)
Serotype 23F	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)
Cross-reactive serotypes	0.047 (0.013 to 0.119)	0.0 (0.0 to 0.044)
Serotype 6A	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)
Serotype 19A	0.035 (0.007 to 0.102)	0.0 (0.0 to 0.044)
Other pneumococcal serotypes	0.023 (0.003 to 0.084)	0.012 (0.0 to 0.066)
Serotype 3	0.012 (0.0 to 0.065)	0.012 (0.0 to 0.066)
Serotype 12F	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)
Serotype 15C	0.0 (0.0 to 0.043)	0.0 (0.0 to 0.044)
H. influenzae ID	0.012 (0.0 to 0.065)	0.012 (0.0 to 0.066)
Non-typeable (NTHI)	0.012 (0.0 to 0.065)	0.012 (0.0 to 0.066)
Other bacteria	0.058 (0.019 to 0.136)	0.012 (0.0 to 0.066)
Neisseria meningitidis	0.023 (0.003 to 0.084)	0.012 (0.0 to 0.066)
Streptococcus pyogenes	0.023 (0.003 to 0.084)	0.0 (0.0 to 0.044)
Moraxella catarrhalis	0.012 (0.0 to 0.065)	0.0 (0.0 to 0.044)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs were reported from Month 0 to end of blinded invasive disease (ID) phase (at least 30 months from study start), in 10PN-PD-DIT-043 subjects.

Adverse event reporting additional description

Solicited and unsolicited AEs were not collected in this study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

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

Reporting group description

Reporting group title

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

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) 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

Ctrl12-18M/043 Group

Reporting group description

Reporting group title

Ctrl7-11M/043 Group

Reporting group description

Reporting group title

10Pn12-18M/043 Group

Reporting group description

Reporting group title

Ctrl-6W-6M/043 Group

Reporting group description

Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (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). The vaccine was administered intramuscularly in the thigh.

Reporting group title

10Pn7-11M/043 Group

Reporting group description

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Only SAEs events were collected as part of this study.

Serious adverse events	10Pn3+1-6W-6M/043 Group	10Pn2+1-6W-6M/043 Group	Ctrl12-18M/043 Group	Ctrl7-11M/043 Group	10Pn12-18M/043 Group	Ctrl-6W-6M/043 Group	10Pn7-11M/043 Group
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 8427 (0.07%)	7 / 9112 (0.08%)	2 / 3020 (0.07%)	2 / 1812 (0.11%)	2 / 6249 (0.03%)	8 / 8872 (0.09%)	3 / 3689 (0.08%)
number of deaths (all causes)	4	4	1	0	0	3	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Foreign body
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0
Vascular disorders
Kawasaki’s disease
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	1 / 6249 (0.02%)	0 / 8872 (0.00%)	1 / 3689 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Gaucher’s disease
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Krabbe’s disease
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocarditis
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	1 / 1812 (0.06%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Febrile convulsion
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	1 / 3020 (0.03%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	1 / 3689 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	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
Syncope
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	1 / 1812 (0.06%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Hypotonic-hyporesponsive episode
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Accidental death
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0
Death
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injection site reaction
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Irritability
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Pyrexia
subjects affected / exposed	2 / 8427 (0.02%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Sudden death
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden infant death syndrome
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	1 / 6249 (0.02%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Vomiting
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Asphyxia
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	1 / 3020 (0.03%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0	0 / 1	0 / 0
Hepatobiliary disorders
Reye’s syndrome
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Cystitis
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Infection
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Laryngitis
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 8427 (0.00%)	1 / 9112 (0.01%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Pneumococcal sepsis
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	1 / 1812 (0.06%)	0 / 6249 (0.00%)	1 / 8872 (0.01%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	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
Sepsis
subjects affected / exposed	1 / 8427 (0.01%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	1 / 3689 (0.03%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	10Pn3+1-6W-6M/043 Group	10Pn2+1-6W-6M/043 Group	Ctrl12-18M/043 Group	Ctrl7-11M/043 Group	10Pn12-18M/043 Group	Ctrl-6W-6M/043 Group	10Pn7-11M/043 Group
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 8427 (0.00%)	0 / 9112 (0.00%)	0 / 3020 (0.00%)	0 / 1812 (0.00%)	0 / 6249 (0.00%)	0 / 8872 (0.00%)	0 / 3689 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

04 Feb 2009

Amendment 1 of the 10PN-PD-DIT-043 (111442) study protocol was developed for the following reasons: (1) Addition of collection of data on respiratory tract infections (RTIs), including acute otitis media (AOM) in a subset of subjects in Turku area; (2) Addition of 6 clusters located in some selected municipalities where no collaboration with health care centres had been set up but where there was opportunity for parent(s) to let their child participate in nested study 10PNPD-DIT-053 (112595) and to receive the same vaccination as in the current study (i.e. Espoo, Vantaa and surroundings municipalities and municipalities surrounding Oulu); and (3) The National Public Health Institute (KTL) and the National Research and Development Centre for Welfare and Health (STAKES) were merged into the National Institute for Health and Welfare (THL).

22 Aug 2011

Amendment 2 was developed for the following reasons: (1) The study enrolment reached only 50% of the initial recruitment plan; therefore, there was a need to redefine the conditions for triggering IPD effectiveness analysis: (a) the study follow-up period for primary analysis on invasive disease (ID) cases was to end on 31 January 2012 (data lock point for ID cases), i.e. at least 30 months after study start. This would allow inclusion of an age-related IPD peak at 1119 months of age in the youngest enrolled subjects and an expected seasonal invasive pneumococcal disease (IPD) peak in the fall of 2011, thereby increasing the potential to accrue additional IPD cases; (b) Reaching a minimum number of 21 culture-confirmed vaccine-type IPD cases in the infant group was no longer a condition for triggering IPD effectiveness analysis because that minimum number was most probably not met due to the lower enrolment numbers. The estimated target number of vaccine-type IPD cases was adjusted accordingly, based on an assumed vaccine efficacy estimate and the currently available information on the total number of IPD cases by age cohort. Taking into account the lower than expected number of enrolled subjects, associated number of overall IPD cases reported so far and impact on power when considering 80% vaccine efficacy for the 2+1 vaccination schedule, it was decided to evaluate the effectiveness of the 10Pn-PD-DiT vaccine to prevent vaccine-type IPD in the infants assigned to a 2+1 vaccination course as a first secondary objective instead of the second primary objective (sequential) but to keep the predefined statistical criteria for success. (2) Following IDMC recommendation, it was decided to have the chest X-rays from the hospital-diagnosed pneumonia cases in the vaccinated population evaluated by an independent review panel according to World Health Organisation (WHO) guidelines for study purposes. The appropriate sections of the protocol were adjusted to reflect this.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A phase III/IV, cluster-randomized, controlled study to evaluate the effectiveness of GlaxoSmithKline Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in reducing the incidence of invasive diseases.

Trial information

Trial information

Subject disposition

Subject disposition

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 (till end of blinded ID FU period)

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 (till end of blinded ID FU period)

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 (till end of blinded ID FU period)

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 (till end of blinded ID FU period)

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 (+ indirect effects on the unvaccinated population)

Secondary: Person Year Rate in the prevention of culture-confirmed invasive disease (ID)- In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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 (+ indirect effects on the unvaccinated population)

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 (+ indirect effects on the unvaccinated population)

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 (+ indirect effects on the unvaccinated population)

Secondary: Person Year Rate in reducing hospital-diagnosed pneumonia - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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 (+ indirect effects on the unvaccinated population)

Secondary: Person Year Rate in prevention of all tympanostomy tube placements - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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 (+ indirect effects on the unvaccinated population)

Secondary: Person Year Rate in prevention of all antimicrobial prescriptions - In children starting vaccination in the 12-18 months schedule (+ indirect effects on the unvaccinated population)

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 SAEs reported during the blinded invasive disease phase, of the study

Secondary: Number of subjects with SAEs reported during the blinded invasive disease phase, of the study

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: 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

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

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

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

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A phase III/IV, cluster-randomized, controlled study to evaluate the effectiveness of GlaxoSmithKline Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in reducing the incidence of invasive diseases.