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Clinical Trial Results:
A phase III, double-blind, randomised, placebo-controlled, multi-center study to assess the efficacy, safety and immunogenicity of two or three doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine given concomitantly with routine EPI vaccinations in healthy infants.

Summary
EudraCT number	2015-001485-26
Trial protocol	Outside EU/EEA
Global end of trial date	30 Jan 2009

Results information
Results version number	v1(current)
This version publication date	20 Apr 2016
First version publication date	23 Jul 2015
Other versions

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

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Trial information

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Sponsor protocol code

102248,111274

ISRCTN number

US NCT number

NCT00241644

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

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

Public contact

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

Scientific contact

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

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

15 Jun 2009

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jan 2009

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2009

Was the trial ended prematurely?

Main objective of the trial

To determine if the GSK Biologicals' HRV vaccine (pooled HRV groups) given concomitantly with routine EPI vaccinations can prevent severe RV GE (>11 on the 20-point Vesikari scoring system) caused by the circulating wild-type RV strains during the period from 2 weeks after the last dose of HRV vaccine or placebo until Visit 6. Criteria: The primary objective will be reached if the lower limit of the 95% CI on vaccine efficacy is > 0%.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Oct 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

South Africa: 3168

Country: Number of subjects enrolled

Malawi: 1773

Worldwide total number of subjects

4941

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

4941

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

Only subjects from Malawi and from Cohort 2 South Africa were asked to continue the study for a second follow-up period (Year 2).

Screening details

Of the total of 4941 subjects enrolled in this study, 2 subjects were allocated a subject number but did not get any study vaccine administered. Hence, only 4939 subjects were considered as 'started'. For the second follow-up period, as mentioned in the protocol the results are presented for Rotarix Pooled and Placebo Groups only.

Period 1 title

First efficacy period (Year 1)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

The study was conducted in a double-blind manner with respect to GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine and placebo. The parents/guardians of the subjects, the study personnel and the investigator were unaware of the administered treatment (HRV vaccine or placebo).

Are arms mutually exclusive

Yes

Rotarix 2-dose Group

Arm description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Arm type

Experimental

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

GSK Biologicals’ HRV vaccine

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Two or Three doses, oral administration.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

One or three doses, oral administration.

Rotarix 3-dose Group

Arm description

Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Arm type

Experimental

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

GSK Biologicals’ HRV vaccine

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Two or Three doses, oral administration.

Placebo Group

Arm description

Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

One or three doses, oral administration.

Number of subjects in period 1 ^[1]	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group
Started	1647	1651	1641
Completed; Visit 6	1420	1383	1392
Completed	1420	1383	1392
Not completed	227	268	249
Return dates not reliable	1	-	-
Consent withdrawn by subject	59	74	81
Adverse event, non-fatal	46	45	45
Non-compliance	2	1	2
Subject's parent passed away	-	1	-
Lost to follow-up	116	142	116
Vaccinated at regular clinic	-	-	1
Protocol deviation	3	5	4

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: withOf the total of 4941 subjects enrolled in this study, 2 subjects were allocated a subject number but did not get any study vaccine administered. Hence, only 4939 subjects were considered as 'started'.

Period 2 title

Second efficacy period (Year 2)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Rotarix 2-dose Group

Arm description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Arm type

Experimental

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

GSK Biologicals’ HRV vaccine

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Two or Three doses, oral administration.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

One or three doses, oral administration.

Rotarix 3-dose Group

Arm description

Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Arm type

Experimental

Investigational medicinal product name

Rotarix™

Investigational medicinal product code

Other name

GSK Biologicals’ HRV vaccine

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Two or Three doses, oral administration.

Placebo Group

Arm description

Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

One or three doses, oral administration.

Number of subjects in period 2 ^[2]	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group
Started	771	754	746
Completed	710	697	682
Not completed	61	57	64
Consent withdrawn by subject	4	3	2
Adverse event, non-fatal	11	9	12
Consenting parent passed away	1	1	2
Lost to follow-up	43	43	46
Protocol deviation	2	1	2

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: For the second follow-up period, as mentioned in the protocol the results are presented for Rotarix Pooled and Placebo Groups only.

Baseline characteristics

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Reporting group title

Rotarix 2-dose Group

Reporting group description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Rotarix 3-dose Group

Reporting group description

Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Placebo Group

Reporting group description

Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines.

Reporting group values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Total
Number of subjects	1647	1651	1641	4939
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	6.3 ( 0.92 )	6.4 ( 0.98 )	6.4 ( 0.97 )	-
Gender categorical
Units: Subjects
Female	811	839	800	2450
Male	836	812	841	2489

Subject analysis set title

Rotarix Pooled Group (Year 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

For some data analyses, the 2 Groups receiving Rotarix (Rotarix 2-dose Group & Rotarix 3-dose Group) were pooled into Rotarix pooled Group.

Subject analysis set title

Rotarix Pooled Group (Year 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

For some data analyses, the 2 Groups receiving Rotarix (Rotarix 2-dose Group & Rotarix 3-dose Group) were pooled into Rotarix pooled Group.

Subject analysis sets values	Rotarix Pooled Group (Year 1)	Rotarix Pooled Group (Year 2)
Number of subjects	3298	1525
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: weeks
arithmetic mean (standard deviation)	6.4 ( 0.95 )	( )
Gender categorical
Units: Subjects
Female	1650
Male	1648

End points

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Reporting group title

Rotarix 2-dose Group

Reporting group description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Rotarix 3-dose Group

Reporting group description

Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Placebo Group

Reporting group description

Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines.

Reporting group title

Rotarix 2-dose Group

Reporting group description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Rotarix 3-dose Group

Reporting group description

Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines.

Reporting group title

Placebo Group

Reporting group description

Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines.

Subject analysis set title

Rotarix Pooled Group (Year 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

For some data analyses, the 2 Groups receiving Rotarix (Rotarix 2-dose Group & Rotarix 3-dose Group) were pooled into Rotarix pooled Group.

Subject analysis set title

Rotarix Pooled Group (Year 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

For some data analyses, the 2 Groups receiving Rotarix (Rotarix 2-dose Group & Rotarix 3-dose Group) were pooled into Rotarix pooled Group.

Primary: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

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End point title

Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain. ^[1]

End point description

Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. This outcome measure concerns subjects in the Rotarix 2-dose Group

End point type

Primary

End point timeframe

From 2 weeks after the last vaccine or placebo dose up to 1 year of age.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1496	1478	1443	2974
Units: Subjects	30	26	70	56

No statistical analyses for this end point

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain, classified by rotavirus type.

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End point title

Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain, classified by rotavirus type.

End point description

Number of subjects presenting with three or more looser than normal stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. Rotavirus types were G1 wild type (WT) and non-G1.

End point type

Secondary

End point timeframe

From 2 weeks after the last vaccine or placebo dose up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1496	1478	1443	2974
Units: Subjects
G1 WT	8	9	23	17
Non-G1	22	17	47	39

No statistical analyses for this end point

Secondary: Number of subjects reporting any rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

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End point title

Number of subjects reporting any rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

End point description

End point type

Secondary

End point timeframe

From 2 weeks after the last vaccine or placebo dose up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1496	1478	1443	2974
Units: Subjects	93	74	174	167

No statistical analyses for this end point

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

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End point title

Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

End point description

End point type

Secondary

End point timeframe

From the first vaccine or placebo dose up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1647	1651	1641	3298
Units: Subjects	37	31	83	68

No statistical analyses for this end point

Secondary: In South Africa, number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

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End point title

In South Africa, number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

End point description

End point type

Secondary

End point timeframe

From 2 weeks after the third dose of vaccine or placebo up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	478	468	468	946
Units: Subjects	5	3	20	8

No statistical analyses for this end point

Secondary: Number of subjects reporting severe gastroenteritis of any cause.

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End point title

Number of subjects reporting severe gastroenteritis of any cause.

End point description

Number of subjects with gastroenteritis (three or more looser than normal stools or watery stools within a day) that scored ≥ 11 on the 20-point Vesikari scoring system.

End point type

Secondary

End point timeframe

From 2 weeks after the last vaccine or placebo dose up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1496	1478	1443	2974
Units: Subjects	134	122	178	256

No statistical analyses for this end point

Secondary: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

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End point title

Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

End point description

RV GE caused by the circulating wild-type rotavirus strain: three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample collected as soon as possible after the symptoms begin.

End point type

Secondary

End point timeframe

From 2 weeks after the last vaccine or placebo dose up to 1 year of age.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1496	1478	1443	2974
Units: Subjects	78	64	156	142

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

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End point title

For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains. ^[2]

End point description

End point type

Secondary

End point timeframe

During the period from 2 weeks after the last dose of vaccine or placebo until study end.

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure concerns subjects in the Placebo group from the first efficacy period and the Rotarix pooled group (Year 1) only.

End point values	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	891	1873
Units: Subjects	81	66

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

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End point title

For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

End point description

End point type

Secondary

End point timeframe

During the period from 1 year of age to study end.

End point values	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	712	1500
Units: Subjects	21	35

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

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End point title

For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains. ^[3]

End point description

End point type

Secondary

End point timeframe

During the period from 2 weeks after the last dose of vaccine or placebo until study end.

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure concerns subjects in the Placebo group from the first efficacy period and the Rotarix pooled group (Year 1) only.

End point values	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	891	1873
Units: Subjects	118	159

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

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End point title

End point description

End point type

Secondary

End point timeframe

During the period from 1 year of age to study end.

End point values	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	712	1500
Units: Subjects	26	58

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

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End point title

For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type. ^[4]

End point description

Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. Rotavirus types were G1 wild type (WT) and non-G1. This outcome measure concerns subjects in the Placebo group from the first efficacy period and the Rotarix pooled group (Year 1) only.

End point type

Secondary

End point timeframe

During the period from 2 weeks after the last dose of vaccine or placebo until study end.

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure concerns subjects in the Placebo group from the first efficacy period and the Rotarix pooled group (Year 1) only.

End point values	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	891	1873
Units: Subjects
G1 WT	20	21
Non-G1	48	60

No statistical analyses for this end point

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

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End point title

End point description

End point type

Secondary

End point timeframe

During the period from 1 year of age to study end.

End point values	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	712	1500
Units: Subjects
G1 WT	11	10
Non-G1	10	25

No statistical analyses for this end point

Secondary: Number of subjects with adverse events (AEs) or serious adverse events (SAEs) leading to drop out.

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End point title

Number of subjects with adverse events (AEs) or serious adverse events (SAEs) leading to drop out.

End point description

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

End point type

Secondary

End point timeframe

From the first dose of vaccine or placebo up to end of the study.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1647	1651	1641	3298
Units: Subjects
Any AEs/SAEs	57	54	56	111

No statistical analyses for this end point

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

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End point title

Number of subjects reporting serious adverse events (SAEs).

End point description

An SAE is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.

End point type

Secondary

End point timeframe

From the first dose of vaccine or placebo up to end of the study.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1647	1651	1641	3298
Units: Subjects
Any SAE(s)	222	199	246	421

No statistical analyses for this end point

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies in initially seronegative subjects.

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End point title

Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies in initially seronegative subjects.

End point description

An initially seronegative subject is a subject whose IgA antibody concentration was below the assay cut-off value of 20 Units per milliliter (U/mL) before administration of the first vaccine dose.

End point type

Secondary

End point timeframe

One month after the last vaccine dose.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	106	115	111	221
Units: U/mL
geometric mean (confidence interval 95%)	56.6 (38.9 to 82.3)	79.4 (54.7 to 115.2)	67.5 (51.9 to 87.8)	23.4 (16.8 to 32.5)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects.

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End point title

Number of seroconverted subjects.

End point description

Seroconverted subjects are defined as subjects with appearance of anti-rotavirus IgA antibody concentration ≥ 20 U/mL in subjects initially (i.e. prior to the first dose of vaccine or placebo) seronegative for rotavirus.

End point type

Secondary

End point timeframe

One month after the last vaccine or placebo dose.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 2)
Number of subjects analysed	106	115	111	221
Units: Subjects	57	72	25	129

No statistical analyses for this end point

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies.

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End point title

Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies.

End point description

Geometric mean concentrations are given as Units per milliliter (U/mL).

End point type

Secondary

End point timeframe

One month after the last vaccine or placebo dose.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1160	1138	1125	2298
Units: U/mL
geometric mean (confidence interval 95%)	72.5 (65.2 to 80.6)	67.9 (60.8 to 75.9)	21.8 (19.8 to 24)	70.2 (65 to 75.8)

No statistical analyses for this end point

Secondary: Number of seropositive subjects.

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End point title

Number of seropositive subjects.

End point description

Seropositive subjects are defined as subjects with anti-rotavirus IgA antibody concentration ≥ 20 U/mL.

End point type

Secondary

End point timeframe

One month after the last vaccine or placebo dose.

End point values	Rotarix 2-dose Group	Rotarix 3-dose Group	Placebo Group	Rotarix Pooled Group (Year 1)
Number of subjects analysed	1160	1138	1125	2298
Units: Subjects	756	706	262	1462

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious adverse events (SAEs): During the entire study period.

Adverse event reporting additional description

The number of occurrences reported for solicited symptoms, adverse events, and serious adverse events were not available for posting. The number of subjects affected by each specific event was indicated as the number of occurrences.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

11.0

Reporting group title

Rotarix 2-dose Group

Reporting group description

Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ (rotavirus vaccine).

Reporting group title

Rotarix 3-dose Group

Reporting group description

Subjects received 3 doses of Rotarix™ (rotavirus vaccine).

Reporting group title

Rotarix pooled Group

Reporting group description

For some data analyses, the 2 Groups receiving Rotarix (Rotarix 2-dose Group & Rotarix 3-dose Group) were pooled into Rotarix pooled Group.

Reporting group title

Placebo Group

Reporting group description

Subjects received 3 doses of placebo.

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: No adverse events (non-serious) with frequency equal to or greater than 5% were reported.

Serious adverse events	Rotarix 2-dose Group	Rotarix 3-dose Group	Rotarix pooled Group	Placebo Group
Total subjects affected by serious adverse events
subjects affected / exposed	222 / 1647 (13.48%)	199 / 1651 (12.05%)	421 / 3298 (12.77%)	246 / 1641 (14.99%)
number of deaths (all causes)	2	2	4	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroblastoma
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Adenoidectomy
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	2 / 1647 (0.12%)	2 / 1651 (0.12%)	4 / 3298 (0.12%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 4	0 / 1
Pyrexia
subjects affected / exposed	1 / 1647 (0.06%)	3 / 1651 (0.18%)	4 / 3298 (0.12%)	4 / 1641 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sudden infant death syndrome
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
Cyst
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Irritability
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Immune system disorders
Immunosuppression
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Reproductive system and breast disorders
Genital rash
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 1647 (0.18%)	2 / 1651 (0.12%)	5 / 3298 (0.15%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	3 / 1647 (0.18%)	0 / 1651 (0.00%)	3 / 3298 (0.09%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 0
Asphyxia
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
Aspiration
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Bronchospasm
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Atelectasis
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnea
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Grunting
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pneumothorax
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Adenoidal hypertrophy
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body aspiration
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Thermal burn
subjects affected / exposed	2 / 1647 (0.12%)	4 / 1651 (0.24%)	6 / 3298 (0.18%)	4 / 1641 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Brachial plexus injury
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fractured skull depressed
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	2 / 1647 (0.12%)	0 / 1651 (0.00%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis chemical
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Therapeutic agent toxicity
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Chemical poisoning
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug toxicity
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Congenital, familial and genetic disorders
Heart disease congenital
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Patent ductus arteriosus
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phimosis
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Tachycardia
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	4 / 1647 (0.24%)	7 / 1651 (0.42%)	11 / 3298 (0.33%)	6 / 1641 (0.37%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 11	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
Convulsion
subjects affected / exposed	1 / 1647 (0.06%)	2 / 1651 (0.12%)	3 / 3298 (0.09%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
Fontanelle bulging
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	2 / 1647 (0.12%)	6 / 1651 (0.36%)	8 / 3298 (0.24%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
Lymphadenitis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic disorder
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Eye disorders
Blindness
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Strabismus
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal disorder
subjects affected / exposed	4 / 1647 (0.24%)	2 / 1651 (0.12%)	6 / 3298 (0.18%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Ileus paralytic
subjects affected / exposed	2 / 1647 (0.12%)	0 / 1651 (0.00%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Vomiting
subjects affected / exposed	3 / 1647 (0.18%)	0 / 1651 (0.00%)	3 / 3298 (0.09%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Food poisoning
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	94 / 1647 (5.71%)	67 / 1651 (4.06%)	161 / 3298 (4.88%)	104 / 1641 (6.34%)
occurrences causally related to treatment / all	0 / 94	0 / 67	0 / 161	0 / 104
deaths causally related to treatment / all	0 / 24	0 / 15	0 / 39	0 / 26
Pneumonia
subjects affected / exposed	55 / 1647 (3.34%)	54 / 1651 (3.27%)	109 / 3298 (3.31%)	64 / 1641 (3.90%)
occurrences causally related to treatment / all	0 / 55	0 / 54	0 / 109	0 / 64
deaths causally related to treatment / all	0 / 14	0 / 13	0 / 27	0 / 19
Bronchopneumonia
subjects affected / exposed	29 / 1647 (1.76%)	25 / 1651 (1.51%)	54 / 3298 (1.64%)	25 / 1641 (1.52%)
occurrences causally related to treatment / all	0 / 29	0 / 25	0 / 54	0 / 25
deaths causally related to treatment / all	0 / 6	0 / 5	0 / 11	0 / 3
Sepsis
subjects affected / exposed	33 / 1647 (2.00%)	28 / 1651 (1.70%)	61 / 3298 (1.85%)	29 / 1641 (1.77%)
occurrences causally related to treatment / all	0 / 33	0 / 28	0 / 61	0 / 29
deaths causally related to treatment / all	0 / 10	0 / 3	0 / 13	0 / 3
Bronchiolitis
subjects affected / exposed	21 / 1647 (1.28%)	17 / 1651 (1.03%)	38 / 3298 (1.15%)	17 / 1641 (1.04%)
occurrences causally related to treatment / all	0 / 21	0 / 17	0 / 38	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Malaria
subjects affected / exposed	19 / 1647 (1.15%)	25 / 1651 (1.51%)	44 / 3298 (1.33%)	33 / 1641 (2.01%)
occurrences causally related to treatment / all	0 / 19	0 / 25	0 / 44	0 / 33
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 4
Upper respiratory tract infection
subjects affected / exposed	7 / 1647 (0.43%)	7 / 1651 (0.42%)	14 / 3298 (0.42%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 7	0 / 7	0 / 14	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	7 / 1647 (0.43%)	4 / 1651 (0.24%)	11 / 3298 (0.33%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 7	0 / 4	0 / 11	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
Pneumocystis jiroveci pneumonia
subjects affected / exposed	4 / 1647 (0.24%)	4 / 1651 (0.24%)	8 / 3298 (0.24%)	5 / 1641 (0.30%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 8	0 / 5
deaths causally related to treatment / all	0 / 3	0 / 3	0 / 6	0 / 3
Pulmonary tuberculosis
subjects affected / exposed	3 / 1647 (0.18%)	3 / 1651 (0.18%)	6 / 3298 (0.18%)	4 / 1641 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 2
Lower respiratory tract infection
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Oral candidiasis
subjects affected / exposed	2 / 1647 (0.12%)	1 / 1651 (0.06%)	3 / 3298 (0.09%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 1647 (0.12%)	0 / 1651 (0.00%)	2 / 3298 (0.06%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	3 / 1647 (0.18%)	0 / 1651 (0.00%)	3 / 3298 (0.09%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	2 / 1647 (0.12%)	1 / 1651 (0.06%)	3 / 3298 (0.09%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis pneumococcal
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
Otitis media acute
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	2 / 1647 (0.12%)	0 / 1651 (0.00%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acquired immunodeficiency syndrome
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
Respiratory tract infection
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Staphylococcal skin infection
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Abscess
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral malaria
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eczema infected
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteremia
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Nosocomial infection
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Parotid abscess
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 1647 (0.00%)	2 / 1651 (0.12%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis neonatal
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Tuberculosis
subjects affected / exposed	1 / 1647 (0.06%)	1 / 1651 (0.06%)	2 / 3298 (0.06%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Varicella
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral tonsillitis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated tuberculosis
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis tuberculous
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perianal abscess
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Keratitis herpetic
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 1647 (0.06%)	0 / 1651 (0.00%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salmonella sepsis
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	3 / 1647 (0.18%)	3 / 1651 (0.18%)	6 / 3298 (0.18%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 4	0 / 1
Kwashiorkor
subjects affected / exposed	3 / 1647 (0.18%)	4 / 1651 (0.24%)	7 / 3298 (0.21%)	8 / 1641 (0.49%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 7	0 / 8
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 5	0 / 1
Malnutrition
subjects affected / exposed	5 / 1647 (0.30%)	0 / 1651 (0.00%)	5 / 3298 (0.15%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
Marasmus
subjects affected / exposed	3 / 1647 (0.18%)	5 / 1651 (0.30%)	8 / 3298 (0.24%)	4 / 1641 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 8	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 3	0 / 5	0 / 3
Metabolic acidosis
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	3 / 1641 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hypernatraemia
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	2 / 1641 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemic syndrome
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Electrolyte imbalance
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hypoglycaemic seizure
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	1 / 1641 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 1647 (0.00%)	1 / 1651 (0.06%)	1 / 3298 (0.03%)	0 / 1641 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0

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

Non-serious adverse events	Rotarix 2-dose Group	Rotarix 3-dose Group	Rotarix pooled Group	Placebo Group
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 1647 (0.00%)	0 / 1651 (0.00%)	0 / 3298 (0.00%)	0 / 1641 (0.00%)

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Were there any global substantial amendments to the protocol? Yes

24 Aug 2005

This protocol was amended to implement the following changes: - To increase the sample size: The assumed attack rate of 2% for severe RV GE for sample size estimation in the original protocol was found to be too optimistic based on the results obtained in several studies with GSK Biologicals' HRV vaccine. A more conservative attack rate of 1.5% was therefore considered and the sample size was revised. - In the context of the increased sample size, to specify the target enrolment in South Africa. - To allow HIV testing according to the national guidelines in south Africa. HIV testing will be performed at Visit 3 in all subjects whose parents/guardians gave consent, followed by a confirmatory test at Visit 4 in HIV positive subjects who are asymptomatic. - To add an additional study visit to communicate results of the confirmatory HIV test to the parents/guardians. - To change method of data collection from Remote Data Entry to Case Report Forms. - Following feedback from the ERCs, changes to reflect local clinical practice for care and treatment were made.

02 Aug 2007

This amendment was done on 2 August 2007 to implement the following changes for the South Africa cohort as recommended by the Rotavirus Vaccine Program (RVP) organization which co-sponsors this study. - To perform an interim analysis on efficacy data collected from Cohort 1 and Cohort 2 in South Africa until the cut off date of 31 August 2007. This interim analysis is performed under the request by RVP to allow early review of African efficacy data to prepare implementation of universal mass vaccination (UMV) in some African countries. The availability of earlier results suggesting favorable efficacy of the vaccine in developing countries in Africa would be useful as an advocacy tool to stimulate policy makers both at global level (e.g. WHO, SAGE, GAVI) and at the country level to prepare for accelerated decision-making and introduction activities in Africa. - To extend follow-up for efficacy until the end of the second consecutive RV season for Cohort 2 South Africa. Also, safety follow-up for SAEs and AEs leading to drop out will be performed for these subjects until the end of the RV season. The follow-up during the second year will also be performed for the cohort in Malawi. Additional follow-up may allow for the estimation of vaccine efficacy, either among all infants over the combined first and second year of life or during the second year of life. Additional follow-up may also provide greater power to investigate other aspects of vaccine efficacy such as protection among infants in these populations with high HIV prevalence, better estimation of strain and dose-specific vaccine efficacy. - To implement a supplementary ICF to allow using post-breast feeding cessation HIV results in the analysis when HIV test is performed.

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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Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

Primary: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain, classified by rotavirus type.

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain, classified by rotavirus type.

Secondary: Number of subjects reporting any rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects reporting any rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: In South Africa, number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: In South Africa, number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects reporting severe gastroenteritis of any cause.

Secondary: Number of subjects reporting severe gastroenteritis of any cause.

Secondary: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

Secondary: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strain.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis (RV GE) caused by the circulating wild-type rotavirus strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects hospitalized and/or with supervised re-hydration therapy due to rotavirus gastroenteritis (RV GE) episode caused by the circulating wild-type RV strains.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

Secondary: For subjects in Cohort 2 South Africa and the cohort in Malawi: Number of subjects with severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus strains, classified by rotavirus type.

Secondary: Number of subjects with adverse events (AEs) or serious adverse events (SAEs) leading to drop out.

Secondary: Number of subjects with adverse events (AEs) or serious adverse events (SAEs) leading to drop out.

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

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

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies in initially seronegative subjects.

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies in initially seronegative subjects.

Secondary: Number of seroconverted subjects.

Secondary: Number of seroconverted subjects.

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies.

Secondary: Geometric mean concentration of anti-rotavirus immunoglobulin A (IgA) antibodies.

Secondary: Number of seropositive subjects.

Secondary: Number of seropositive subjects.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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