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Clinical Trial Results:
A phase IIIA, randomized, observer-blind, controlled, multinational consistency study to evaluate the immunogenicity and safety of GSK Biologicals' MMR vaccine (GSK209762) (Priorix) compared to Merck & Co., Inc.’s MMR vaccine (M-M-R II), as a first dose, both co-administered with Varivax, Havrix and Prevnar 13 (subset of children) to healthy children 12 to 15 months of age.

Summary
EudraCT number	2011-004891-12
Trial protocol	EE FI ES
Global end of trial date	16 Apr 2015

Results information
Results version number	v2(current)
This version publication date	16 Jun 2018
First version publication date	30 Jul 2016
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

115648

ISRCTN number

US NCT number

NCT01702428

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

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

Public contact

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)2089 904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)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

09 Feb 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

1. To demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of seroresponse rates to measles, mumps and rubella viruses at Day 42. 2. To demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of geometric mean concentrations (GMCs) for antibodies to measles, mumps and rubella viruses at Day 42. 3. To demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR (for the two pooled lots) vaccine in terms of seroresponse rates to measles, mumps and rubella viruses at Day 42. 4. To demonstrate non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR (for the two pooled lots) vaccine in terms of GMCs for antibodies to measles, mumps and rubella viruses at Day 42. 5. To demonstrate an acceptable immune response for INV_MMR in terms of seroresponse rates to measles, mumps and rubella viruses at Day 42.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Nov 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 256

Country: Number of subjects enrolled

Estonia: 501

Country: Number of subjects enrolled

Finland: 1350

Country: Number of subjects enrolled

Mexico: 394

Country: Number of subjects enrolled

United States: 2515

Worldwide total number of subjects

5016

EEA total number of subjects

2107

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)

5016

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

13 subjects from 5016 were allocated subject number but no study vaccine was administered. Therefore, the number of subjects started is 5003.

Screening details

Sub-cohorts for this study were as follows: • US sub-cohort: Subjects recruited in US and received INV_MMR or COM_MMR co-administered with Varivax (VV), Havrix (HAV) and Prevnar (PCV-13) vaccines at Visit 1 (Day 0). • Non-US sub-cohort: Subjects recruited outside US and received INV_MMR or COM_MMR co-administered with VV and HAV vaccines at Day 0.

Number of subjects started

5016

Number of subjects completed

5003

Reason: Number of subjects

No study vaccine administered: 13

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind ^[1]

Roles blinded

Subject, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The study was conducted in a double-blind fashion, with regard to the lot-to-lot consistency evaluation of the three INV_MMR vaccine lots and in an observer-blind fashion for the comparison of the pooled lots of INV_MMR vaccine versus the pooled COM_MMR vaccine lots.

Are arms mutually exclusive

Yes

INV_MMR_L1 Group

Arm description

Subjects received 1 dose of GSK's candidate combined measles, mumps and rubella (MMR) investigational vaccine (INV_MMR) Lot 1 (L1) co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Arm type

Experimental

Investigational medicinal product name

Priorix

Investigational medicinal product code

Other name

GSK Biologicals' live attenuated measles, mumps and rubella vaccine (GSK209762)

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of MMR vaccine which was administered subcutaneously in the triceps region of the left arm.

Investigational medicinal product name

Varivax

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of VV vaccine which was administered subcutaneously in the triceps region of the right arm.

Investigational medicinal product name

Havrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of HAV vaccine which was administered intramuscularly in the anterolateral region of the right thigh.

Investigational medicinal product name

Prevnar 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

US subjects received 1 dose of PCV-13 vaccine which was administered intramuscularly in the anterolateral region of the left thigh.

INV_MMR_L2 Group

Arm description

Subjects received 1 dose of GSK's candidate combined measles, mumps and rubella (MMR) investigational vaccine (INV_MMR) Lot 2 (L2) co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Arm type

Experimental

Investigational medicinal product name

Priorix

Investigational medicinal product code

Other name

GSK Biologicals' live attenuated measles, mumps and rubella vaccine (GSK209762)

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of MMR vaccine which was administered subcutaneously in the triceps region of the left arm.

Investigational medicinal product name

Varivax

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of VV vaccine which was administered subcutaneously in the triceps region of the right arm.

Investigational medicinal product name

Havrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of HAV vaccine which was administered intramuscularly in the anterolateral region of the right thigh.

Investigational medicinal product name

Prevnar 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

US subjects received 1 dose of PCV-13 vaccine which was administered intramuscularly in the anterolateral region of the left thigh.

INV_MMR_L3 Group

Arm description

Subjects received 1 dose of GSK's candidate combined measles, mumps and rubella (MMR) investigational vaccine (INV_MMR) Lot 3 (L3) co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Arm type

Experimental

Investigational medicinal product name

Priorix

Investigational medicinal product code

Other name

GSK Biologicals' live attenuated measles, mumps and rubella vaccine (GSK209762)

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of MMR vaccine which was administered subcutaneously in the triceps region of the left arm.

Investigational medicinal product name

Varivax

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of VV vaccine which was administered subcutaneously in the triceps region of the right arm.

Investigational medicinal product name

Havrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of HAV vaccine which was administered intramuscularly in the anterolateral region of the right thigh.

Investigational medicinal product name

Prevnar 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

US subjects received 1 dose of PCV-13 vaccine which was administered intramuscularly in the anterolateral region of the left thigh.

COM_MMR Group

Arm description

Subjects received 1 dose of COM_MMR Lot 1 and Lot 2 co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively. Pooled analysis was conducted for this group.

Arm type

Active comparator

Investigational medicinal product name

Varivax

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of VV vaccine which was administered subcutaneously in the triceps region of the right arm.

Investigational medicinal product name

Havrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of HAV vaccine which was administered intramuscularly in the anterolateral region of the right thigh.

Investigational medicinal product name

Prevnar 13

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

US subjects received 1 dose of PCV-13 vaccine which was administered intramuscularly in the anterolateral region of the left thigh.

Investigational medicinal product name

M-M-R II

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1 dose of MMR vaccine which was administered subcutaneously in the triceps region of the left arm.

Notes
[1] - The roles blinded appear to be inconsistent with a double blind trial.
Justification: The study was conducted in a double-blind fashion, with regard to the lot-to-lot consistency evaluation of the three INV_MMR vaccine lots and in an observer-blind fashion for the comparison of the pooled lots of INV_MMR vaccine versus COM_MMR vaccine.

Number of subjects in period 1 ^[2]	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group
Started	1239	1232	1243	1289
Completed	1175	1162	1190	1232
Not completed	64	70	53	57
Lost Health Plan	3	5	-	2
Consent withdrawn by subject	21	23	14	10
Adverse event, non-fatal	2	-	-	-
Parents cannot assist to site	1	-	1	-
Mother transferred care	-	1	-	-
Lost to follow-up	33	41	37	44
Parents too busy	1	-	-	-
Protocol deviation	3	-	1	-
Lost Coverage	-	-	-	1

Notes
[2] - 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: 13 subjects from 5016 were allocated subject number but no study vaccine was administered. Therefore, the number of subjects started is 5003.

Baseline characteristics

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Reporting group title

INV_MMR_L1 Group

Reporting group description

Reporting group title

INV_MMR_L2 Group

Reporting group description

Reporting group title

INV_MMR_L3 Group

Reporting group description

Reporting group title

COM_MMR Group

Reporting group description

Reporting group values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	Total
Number of subjects	1239	1232	1243	1289
Age categorical
Units: Subjects
Age continuous
Units: months
arithmetic mean (standard deviation)	12.3 ( 0.7 )	12.3 ( 0.7 )	12.3 ( 0.7 )	12.3 ( 0.7 )	-
Gender categorical
Units: Subjects
Female	607	594	615	618	2434
Male	632	638	628	671	2569
Race/Ethnicity, Customized
Units: Subjects
White - Arabic / North African Heritage	5	6	2	7	20
Asian - Central/South Asian Heritage	14	6	7	9	36
Other	170	155	162	163	650
Native Hawaiian or Other Pacific Islander	3	1	5	2	11
American Indian or Alaskan Native	25	37	33	31	126
White - Caucasian / European Heritage	932	938	944	970	3784
Asian - South East Asian Heritage	21	25	21	26	93
African Heritage / African American	60	52	57	70	239
Asian - Japanese Heritage	1	2	2	1	6
Asian - East Asian Heritage	8	10	10	10	38

End points

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Reporting group title

INV_MMR_L1 Group

Reporting group description

Reporting group title

INV_MMR_L2 Group

Reporting group description

Reporting group title

INV_MMR_L3 Group

Reporting group description

Reporting group title

COM_MMR Group

Reporting group description

Subject analysis set title

INV_MMR Group

Subject analysis set type

Per protocol

Subject analysis set description

This group included subjects from INV_MMR _L1, INV_MMR _L2 and INV_MMR _L3 groups for whom pooled analysis was conducted in addition to lot-to-lot consistency.

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value

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End point title

Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value ^[1]

End point description

Seroresponse was defined as post-vaccination anti-measles virus antibody concentration ≥200 milli International Unit/Milliliter (mIU/mL) among subjects who were seronegative (antibody concentration <150 mIU/mL) before vaccination. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[1] - 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: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1083	1069	1096
Units: Percentage of subjects
number (confidence interval 95%)
Anti-measles ≥ 150 mIU/mL	98.2 (97.3 to 98.9)	98.9 (98.0 to 99.4)	98.1 (97.1 to 98.8)
Anti-measles ≥ 200 mIU/mL	98.1 (97.1 to 98.8)	98.6 (97.7 to 99.2)	97.8 (96.8 to 98.6)

Statistical analysis 1

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L2 Group) in percentage of subjects with anti-measles antibody concentration ≥200 mIU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2152

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Difference in seroresponse rate

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-1.69

upper limit

0.58

Notes
[2] - For each pair-wise comparison, the 2-sided 95% confidence interval (CI) on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to measles virus.

Statistical analysis 2

Statistical analysis description

Difference between groups (INV_MMR_L2 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-measles antibody concentration ≥200 mIU/mL.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2165

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

1.98

Notes
[3] - For each pair-wise comparison, the 2-sided 95% confidence interval (CI) on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to measles virus.

Statistical analysis 3

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-measles antibody concentration ≥200 mIU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2179

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.98

upper limit

1.5

Notes
[4] - For each pair-wise comparison, the 2-sided 95% confidence interval (CI) on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to measles virus.

Primary: Anti-measles virus antibody concentrations

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End point title

Anti-measles virus antibody concentrations ^[5]

End point description

Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[5] - 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: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of geometric mean concentrations (GMCs). This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1083	1069	1096
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	2970.3 (2813.2 to 3136.2)	3023.6 (2864.5 to 3191.6)	3058.3 (2893.9 to 3232.0)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L2 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2152

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.06

Notes
[6] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 2

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L3 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2179

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.05

Notes
[7] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 3

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L1 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2152

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.09

Notes
[8] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 4

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L3 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2165

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.06

Notes
[9] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 5

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L1 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2179

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.11

Notes
[10] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 6

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L2 Group) for antibodies to measles virus at Day 42.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2165

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.09

Notes
[11] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value

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End point title

Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value ^[12]

End point description

Seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥10 ELISA Unit/Milliliter (EU/mL) among subjects who were seronegative (antibody concentrations <5 EU/mL) before vaccination. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1062	1047	1078
Units: Percentage of subjects
number (confidence interval 95%)
Anti-mumps ≥ 5 EU/mL	99.7 (99.2 to 99.9)	99.3 (98.6 to 99.7)	99.2 (98.4 to 99.6)
Anti-mumps ≥ 10 EU/mL	98.6 (97.7 to 99.2)	98.6 (97.6 to 99.2)	98.0 (96.9 to 98.7)

Statistical analysis 1

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L2 Group) in percentage of subjects with anti-mumps antibody concentration ≥10 EU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2109

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

1.09

Notes
[13] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to mumps virus.

Statistical analysis 2

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-mumps antibody concentration ≥10 EU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2140

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.81

Notes
[14] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to mumps virus.

Statistical analysis 3

Statistical analysis description

Difference between groups (INV_MMR_L2 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-mumps antibody concentration ≥10 EU/mL.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2125

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

1.79

Notes
[15] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to mumps virus.

Primary: Anti-mumps virus antibody concentration

Top of page

End point title

Anti-mumps virus antibody concentration ^[16]

End point description

Antibody concentrations were expressed as GMCs in EU/mL. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1062	1047	1078
Units: EU/mL
geometric mean (confidence interval 95%)
EU/mL	71.7 (68.3 to 75.2)	76.9 (73.2 to 80.8)	69.0 (65.5 to 72.7)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L2 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2109

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

Notes
[17] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Statistical analysis 2

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L3 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2140

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.11

Notes
[18] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Statistical analysis 3

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L1 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2109

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[19]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.15

Notes
[19] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Statistical analysis 4

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L3 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L3 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2125

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[20]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.19

Notes
[20] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Statistical analysis 5

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L1 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2140

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.03

Notes
[21] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Statistical analysis 6

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L2 Group) for antibodies to mumps virus at Day 42.

Comparison groups

INV_MMR_L3 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2125

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[22]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

0.96

Notes
[22] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to mumps.

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value

Top of page

End point title

Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value ^[23]

End point description

Seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥10 International Unit/Milliliter (IU/mL) among subjects who were seronegative (antibody concentrations <4 IU/mL) before vaccination. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1083	1067	1095
Units: Percentage of subjects
number (confidence interval 95%)
Anti-rubella ≥ 4 IU/mL	99.4 (98.8 to 99.8)	99.7 (99.2 to 99.9)	99.4 (98.7 to 99.7)
Anti-rubella ≥ 10 IU/mL	97.2 (96.1 to 98.1)	97.1 (95.9 to 98.0)	97.7 (96.6 to 98.5)

Statistical analysis 1

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L2 Group) in percentage of subjects with anti-rubella antibody concentration ≥10 IU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L2 Group

Number of subjects included in analysis

2150

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[24]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

1.58

Notes
[24] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to rubella virus.

Statistical analysis 2

Statistical analysis description

Difference between groups (INV_MMR_L1 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-rubella antibody concentration ≥10 IU/mL.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2178

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

Method

Parameter type

Difference in seroresponse rate

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.86

upper limit

0.86

Notes
[25] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to rubella virus.

Statistical analysis 3

Statistical analysis description

Difference between groups (INV_MMR_L2 Group minus INV_MMR_L3 Group) in percentage of subjects with anti-rubella antibody concentration ≥10 IU/mL.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2162

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

Parameter type

Difference in seroresponse rate

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-2.02

upper limit

0.74

Notes
[26] - For each pair-wise comparison, the 2-sided 95% CI on the lot difference in seroresponse rates should be within the [-5%;5%] margin for antibodies to rubella virus.

Primary: Anti-rubella virus antibody concentration

Top of page

End point title

Anti-rubella virus antibody concentration ^[27]

End point description

Antibody concentrations were expressed as GMCs in IU/mL. This outcome measure is applicable to reporting groups INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 as analysis was performed on subjects who received one of the lots of INV_MMR vaccine.

End point type

Primary

End point timeframe

At Day 42

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the consistency of three manufacturing lots of INV_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR_L1, INV_MMR_L2 and INV_MMR_L3 Groups).

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group
Number of subjects analysed	1083	1067	1095
Units: IU/mL
geometric mean (confidence interval 95%)
IU/mL	57.2 (54.4 to 60.1)	53.1 (50.5 to 55.7)	57.0 (54.3 to 59.8)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L2 Group) for antibodies to rubella virus at Day 42. .

Comparison groups

INV_MMR_L2 Group v INV_MMR_L1 Group

Number of subjects included in analysis

2150

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[28]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.15

Notes
[28] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 2

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L1 Group divided by INV_MMR_L3 Group) for antibodies to rubella virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2178

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[29]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.07

Notes
[29] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 3

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L1 Group) for antibodies to rubella virus at Day 42.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L1 Group

Number of subjects included in analysis

2150

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[30]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

0.99

Notes
[30] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 4

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L2 Group divided by INV_MMR_L3 Group) for antibodies to rubella virus at Day 42.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2162

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[31]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

0.99

Notes
[31] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 5

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L1 Group) for antibodies to rubella virus at Day 42.

Comparison groups

INV_MMR_L1 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2178

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[32]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.07

Notes
[32] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Statistical analysis 6

Statistical analysis description

Adjusted GMC ratio (INV_MMR_L3 Group divided by INV_MMR_L2 Group) for antibodies to rubella virus at Day 42.

Comparison groups

INV_MMR_L2 Group v INV_MMR_L3 Group

Number of subjects included in analysis

2162

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[33]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.15

Notes
[33] - For each pair-wise comparison, the 2-sided 95% CI on the lot ratio should be within the [0.67;1.5] margin for antibodies to measles.

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Top of page

End point title

Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value in pooled MMR groups ^[34]

End point description

Seroresponse was defined as post-vaccination anti-measles virus antibody concentration ≥200 mIU/mL among subjects who were seronegative (antibody concentration <150 mIU/mL) before vaccination. Criteria to demonstrate an acceptable immune response for INV_MMR in terms of seroresponse rates to measles virus at Day 42: The LL of 2-sided 95% CI for the seroresponse rate for the pooled INV_MMR lots is ≥90% for antibodies to measles virus.

End point type

Primary

End point timeframe

At Day 42

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1137	3248
Units: Percentage of subjects
number (confidence interval 95%)
Anti-measles ≥ 150 mIU/mL	98.1 (97.1 to 98.8)	98.4 (97.9 to 98.8)
Anti-measles ≥ 200 mIU/mL	98.0 (97.0 to 98.7)	98.2 (97.6 to 98.6)

Statistical analysis 1

Statistical analysis description

Difference in percentage (INV_MMR Group minus COM_MMR Group) of subjects with anti-measles antibody concentration at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4385

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

1.25

Notes
[35] - The Lower Limit (LL) of 2-sided 95 % CI for the difference in seroresponse (INV_MMR Group minus COM_MMR Group) should be ≥-5% for antibodies to measles virus.

Primary: Anti-measles virus antibody concentrations in pooled MMR groups

Top of page

End point title

Anti-measles virus antibody concentrations in pooled MMR groups ^[36]

End point description

Antibody concentrations were expressed as GMCs in mIU/mL.

End point type

Primary

End point timeframe

At Day 42

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1137	3248
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	3074.4 (2911.0 to 3246.9)	3017.4 (2923.9 to 3113.8)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for antibodies to measles virus at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4385

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.05

Notes
[37] - The LL of the 2-sided 95% CI on GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.67 for antibodies to measles virus.

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Top of page

End point title

Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value in pooled MMR groups ^[38]

End point description

Seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥10 EU/mL among subjects who were seronegative (antibody concentrations <5 EU/mL) before vaccination.

End point type

Primary

End point timeframe

At Day 42

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1107	3187
Units: Percentage of subjects
number (confidence interval 95%)
Anti-mumps ≥ 5 EU/mL	99.3 (98.6 to 99.7)	99.4 (99.1 to 99.6)
Anti-mumps ≥ 10 EU/mL	97.6 (96.5 to 98.4)	98.4 (97.9 to 98.8)

Statistical analysis 1

Statistical analysis description

Difference in percentage (INV_MMR Group minus COM_MMR Group) of subjects with anti-mumps antibody concentration at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4294

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[39]

Method

Parameter type

Difference in seroresponse rate

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

1.96

Notes
[39] - The LL of 2-sided 95 % CI for the difference in seroresponse (INV_MMR Group minus COM_MMR Group) should be ≥-5% for antibodies to mumps virus.

Primary: Anti-mumps virus antibody concentration in pooled MMR groups

Top of page

End point title

Anti-mumps virus antibody concentration in pooled MMR groups ^[40]

End point description

Antibody concentrations were expressed as GMCs in EU/mL.

End point type

Primary

End point timeframe

At Day 42

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1107	3187
Units: EU/mL
geometric mean (confidence interval 95%)
EU/mL	69.1 (65.7 to 72.7)	72.4 (70.4 to 74.5)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for antibodies to mumps virus at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4294

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[41]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.11

Notes
[41] - The LL of the 2-sided 95% CI on GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.67 for antibodies to mumps virus.

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Top of page

End point title

Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value in pooled MMR groups ^[42]

End point description

Seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥10 IU/mL among subjects who were seronegative (antibody concentrations <4 IU/mL) before vaccination. Criteria to demonstrate an acceptable immune response for INV_MMR in terms of seroresponse rates to rubella virus at Day 42: The LL of 2-sided 95% CI for the seroresponse rate for the pooled INV_MMR lots is ≥90% for antibodies to rubella virus.

End point type

Primary

End point timeframe

At Day 42

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1135	3245
Units: Percentage of subjects
number (confidence interval 95%)
Anti-rubella ≥ 4 IU/mL	99.6 (99.0 to 99.9)	99.5 (99.2 to 99.7)
Anti-rubella ≥ 10 IU/mL	98.5 (97.6 to 99.1)	97.3 (96.7 to 97.9)

Statistical analysis 1

Statistical analysis description

Difference in percentage (INV_MMR Group minus COM_MMR Group) of subjects with anti-rubella antibody concentration at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4380

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[43]

Method

Parameter type

Difference in seroresponse rate

Point estimate

-1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

-0.15

Notes
[43] - The LL of 2-sided 95 % CI for the difference in seroresponse (INV_MMR Group minus COM_MMR Group) should be ≥-5% for antibodies to rubella virus.

Primary: Anti-rubella virus antibody concentration in pooled MMR groups

Top of page

End point title

Anti-rubella virus antibody concentration in pooled MMR groups ^[44]

End point description

Antibody concentrations were expressed as GMCs in IU/mL.

End point type

Primary

End point timeframe

At Day 42

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1135	3245
Units: IU/mL
geometric mean (confidence interval 95%)
IU/mL	64.0 (61.1 to 67.0)	55.7 (54.2 to 57.3)

Statistical analysis 1

Statistical analysis description

Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for antibodies to rubella virus at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

4380

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[45]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

0.92

Notes
[45] - The LL of the 2-sided 95% CI on GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.67 for antibodies to measles virus.

Secondary: Percentage of subjects with an anti-Varicella Zoster Virus (VZV) antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

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End point title

Percentage of subjects with an anti-Varicella Zoster Virus (VZV) antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups ^[46]

End point description

Seroresponse was defined as post-vaccination anti-VZV antibody concentration ≥75 mIU/mL among subjects who were seronegative (antibody concentration <25 mIU/mL) before vaccination.

End point type

Secondary

End point timeframe

At Day 42

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of seroresponse rates. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	540	1492
Units: Percentage of subjects
number (confidence interval 95%)
Anti-VZV ≥ 25 mIU/mL	99.6 (98.7 to 100)	99.7 (99.3 to 99.9)
Anti-VZV ≥ 75 mIU/mL	90.9 (88.2 to 93.2)	92.2 (90.7 to 93.5)

Statistical analysis 1

Statistical analysis description

In US sub-cohort: Difference in percentage (INV_MMR Group minus COM_MMR Group) of subjects with anti-VZV antibody concentration at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[47]

Method

Parameter type

Difference in seroresponse rate

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

4.29

Notes
[47] - The LL of 2-sided 95 % CI for the difference in seroresponse (pooled INV_MMR Group minus pooled COM_MMR Group) should be ≥-10% for antibodies to VZV.

Secondary: Anti-VZV virus antibody concentration in US sub-cohort of pooled MMR groups

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End point title

Anti-VZV virus antibody concentration in US sub-cohort of pooled MMR groups ^[48]

End point description

Antibody concentrations were expressed as GMCs in mIU/mL.

End point type

Secondary

End point timeframe

At Day 42

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	540	1492
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	167.2 (158.2 to 176.7)	169.6 (164.3 to 175)

Statistical analysis 1

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for antibodies to VZV virus at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[49]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.08

Notes
[49] - The LL of the 2-sided 95% CI on GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.67 for antibodies to VZV.

Secondary: Percentage of subjects with an anti-HAV antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

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End point title

Percentage of subjects with an anti-HAV antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups ^[50]

End point description

Percentage of subjects with an Anti-HAV antibody concentration equal to or above 15 mIU/mL were reported.

End point type

Secondary

End point timeframe

At Day 42

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to assess the immunogenicity of HAV vaccine with respect to the seroresponse rates for antibodies to HAV in the pooled INV_MMR group in contrast to the COM_MMR vaccine groups. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	285	783
Units: Percentage of subjects
number (confidence interval 95%)
Percentage of subjects	87.4 (82.9 to 91.0)	88.9 (86.5 to 91.0)

No statistical analyses for this end point

Secondary: Anti-HAV antibody concentrations in US sub-cohort of pooled MMR groups

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End point title

Anti-HAV antibody concentrations in US sub-cohort of pooled MMR groups ^[51]

End point description

Antibody concentrations were expressed as GMCs in mIU/mL.

End point type

Secondary

End point timeframe

At Day 42

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	285	783
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	42.4 (38.1 to 47.2)	42.0 (39.3 to 44.8)

Statistical analysis 1

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for antibodies to HAV virus at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1068

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[52]

Method

ANOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.11

Notes
[52] - The LL of the 2-sided 95% CI on GMC ratio (INV_MMR Group over COM_MMR Group) was ≥0.5 for antibodies to HAV virus.

Secondary: Anti-S.pneumoniae antibody concentration in US sub-cohort of pooled MMR groups

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End point title

Anti-S.pneumoniae antibody concentration in US sub-cohort of pooled MMR groups ^[53]

End point description

Antibody concentrations were expressed as GMCs in microgram/Milliliter (µg/mL).

End point type

Secondary

End point timeframe

At Day 42

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results for this end point were tabulated to demonstrate the non-inferiority of INV_MMR (for the three pooled lots) compared to COM_MMR vaccine in terms of GMCs. This endpoint therefore presents the results for groups applicable for this analysis (i.e., INV_MMR and COM_MMR Groups).

End point values	COM_MMR Group	INV_MMR Group
Number of subjects analysed	266	759
Units: µg/mL
geometric mean (confidence interval 95%)
anti-PnPS 1 antibody (N = 266; 759)	2.425 (2.195 to 2.679)	2.257 (2.121 to 2.402)
anti-PnPS 3 antibody (N = 265; 758)	0.496 (0.454 to 0.542)	0.506 (0.481 to 0.533)
anti-PnPS 4 antibody (N = 266; 753)	1.872 (1.676 to 2.091)	1.618 (1.518 to 1.725)
anti-PnPS 5 antibody (N = 266; 757)	2.280 (2.085 to 2.493)	2.106 (1.991 to 2.228)
anti-PnPS 6A antibody (N = 266; 759)	5.743 (5.233 to 6.304)	5.840 (5.508 to 6.192)
anti-PnPS 6B antibody (N = 266; 758)	5.838 (5.239 to 6.505)	5.872 (5.504 to 6.265)
anti-PnPS 7F antibody (N = 266; 758)	3.814 (3.484 to 4.176)	3.691 (3.489 to 3.905)
anti-PnPS 9V antibody (N = 266; 759)	2.282 (2.065 to 2.521)	2.318 (2.183 to 2.461)
anti-PnPS 14 antibody (N = 266; 757)	7.053 (6.368 to 7.811)	6.578 (6.155 to 7.029)
anti-PnPS 18C antibody (N = 265; 759)	2.217 (1.990 to 2.470)	2.102 (1.973 to 2.241)
anti-PnPS 19A antibody (N = 265; 759)	4.821 (4.372 to 5.317)	4.731 (4.461 to 5.017)
anti-PnPS 19F antibody (N = 266; 759)	4.260 (3.872 to 4.687)	4.251 (4.013 to 4.504)
anti-PnPS 23F antibody (N = 256; 742)	2.291 (2.025 to 2.592)	2.198 (2.051 to 2.355)

Statistical analysis 1

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 1 antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[54]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.05

Notes
[54] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 2

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 3 antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[55]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.08

Notes
[55] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 3

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 4 antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[56]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

0.98

Notes
[56] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 4

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 5 antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[57]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.01

Notes
[57] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 5

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 6A antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[58]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.11

Notes
[58] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 6

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 6B antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[59]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.09

Notes
[59] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 7

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 7F antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[60]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.03

Notes
[60] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 8

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 9V antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[61]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.08

Notes
[61] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 9

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 14 antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[62]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.02

Notes
[62] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 10

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 18C antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[63]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.02

Notes
[63] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 11

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 19A antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[64]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.07

Notes
[64] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 12

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 19F antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[65]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.06

Notes
[65] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Statistical analysis 13

Statistical analysis description

In US sub-cohort: Adjusted GMC ratio (INV_MMR Group divided by COM_MMR Group) for anti-PnPS 23F antibody at Day 42.

Comparison groups

COM_MMR Group v INV_MMR Group

Number of subjects included in analysis

1025

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[66]

Method

ANCOVA

Parameter type

Adjusted GMC ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.06

Notes
[66] - The LL of the 2-sided 95% CI for GMC ratio (INV_MMR Group over COM_MMR Group) should be ≥0.5 for antibodies to for antibodies to PS serotypes.

Secondary: Number of subjects with any solicited local adverse events (AEs)

Top of page

End point title

Number of subjects with any solicited local adverse events (AEs)

End point description

Assessed solicited local AEs were pain, redness and swelling. Any = Occurrence of the symptom regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 4-days (Days 0-3) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1186	1175	1194	1242	3555
Units: Participants
Any Pain	331	315	273	349	919
Any Redness	296	273	301	313	870
Any Swelling	116	99	103	133	318

No statistical analyses for this end point

Secondary: Number of subjects with any solicited general AEs

Top of page

End point title

Number of subjects with any solicited general AEs

End point description

Assessed solicited general AEs were drowsiness, irritability and loss of appetite. Any = Occurrence of the symptom regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 15-days (Days 0-14) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1190	1176	1200	1243	3566
Units: Participants
Any Drowsiness	533	535	533	586	1601
Any Irritability/fussiness	764	729	765	819	2258
Any Loss of appetite	546	536	526	548	1608

No statistical analyses for this end point

Secondary: Number of subjects reporting any fever

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End point title

Number of subjects reporting any fever

End point description

Any fever = Fever ≥ 38°C.

End point type

Secondary

End point timeframe

During the 43-days (Days 0-42) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1190	1176	1200	1243	3566
Units: Participants
Participants	404	422	418	412	1244

No statistical analyses for this end point

Secondary: Number of subjects reporting any rash

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End point title

Number of subjects reporting any rash

End point description

Assessed were any localized or generalized rash, rash with fever, varicella-like rash, measles/rubella-like rash. Any = Occurrence of the symptom regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 43-days (Days 0-42) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1190	1176	1200	1243	3566
Units: Participants
Any Localized or Generalized	352	331	360	378	1043
Any with fever	106	123	118	104	347
Any Varicella like	87	78	85	85	250
Any Measles/Rubella like	71	88	76	77	235

No statistical analyses for this end point

Secondary: Number of subjects reporting any MMR specific solicited AEs

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End point title

Number of subjects reporting any MMR specific solicited AEs

End point description

Assessed MMR specific solicited AEs were any suspected signs of meningism including febrile convulsions and parotid/salivary gland swelling. Any = Occurrence of the symptom regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 43-days (Days 0-42) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1190	1176	1200	1243	3566
Units: Participants
Any febrile convulsion	4	1	5	3	10
Any parotid/salivary gland swelling	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects reporting any unsolicited AEs

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End point title

Number of subjects reporting any unsolicited AEs

End point description

Unsolicited adverse event (AE) was defined as any adverse event reported in addition to those solicited during the clinical study and also any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = Occurrence of the symptom regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

During the 43-days (Days 0-42) post-vaccination period

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1239	1232	1243	1289	3714
Units: Participants
Participants	615	633	609	618	1857

No statistical analyses for this end point

Secondary: Number of subjects reporting AEs of specific interest

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End point title

Number of subjects reporting AEs of specific interest

End point description

AEs of specific interest included new onset chronic disease (NOCD) (e.g., autoimmune disorders, asthma, type I diabetes, vasculitis, celiac disease, conditions associated with sub-acute or chronic thrombocytopenia and allergies) and AEs prompting emergency room (ER) visits.

End point type

Secondary

End point timeframe

From Day 0 through the end of study (Day 180)

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1239	1232	1243	1289	3714
Units: Participants
NOCDs	40	39	49	48	128
AEs prompting ER visits	123	116	136	134	375

No statistical analyses for this end point

Secondary: Number of subjects reporting any Serious adverse events (SAEs)

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End point title

Number of subjects reporting any Serious adverse events (SAEs)

End point description

SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity. Any SAE = Occurrence of SAE regardless of intensity grade or relation to vaccination.

End point type

Secondary

End point timeframe

From Day 0 through the end of study (Day 180)

End point values	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	COM_MMR Group	INV_MMR Group
Number of subjects analysed	1239	1232	1243	1289	3714
Units: Participants
Participants	21	28	28	25	77

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs: From Day 0 through the end of study (Day-180); Solicited local and general symptoms: During the 4-day (Day 0-3) and 15-days (Day 0-14) post-vaccination period; Unsolicited adverse events: During the 43-days (Day 0-42) post-vaccination period.

Adverse event reporting additional description

The analysis of the solicited symptoms was based on the Total Vaccinated cohort which included only children/doses with documented safety data (i.e., symptom screen/sheet completed).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

INV_MMR_L1 Group

Reporting group description

Subjects received 1 dose of INV_MMR_L1 vaccine co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Reporting group title

INV_MMR_L2 Group

Reporting group description

Subjects received 1 dose of INV_MMR_L2 vaccine co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Reporting group title

INV_MMR_L3 Group

Reporting group description

Subjects received 1 dose of INV_MMR_L3 vaccine co-administered with VV and HAV vaccines at Visit 1 (Day 0). All US subjects were also given PCV-13 vaccine. The MMR vaccine was administered subcutaneously in the triceps region of the left arm while the VV vaccine was administered subcutaneously in the triceps region of the right arm. HAV and PCV-13 vaccines were administered intramuscularly in the anterolateral region of the right and left thigh, respectively.

Reporting group title

INV_MMR Group

Reporting group description

This group included subjects from INV_MMR _L1, INV_MMR _L2 and INV_MMR _L3 groups for whom pooled analysis was conducted in addition to lot-to-lot consistency.

Reporting group title

COM_MMR Group

Reporting group description

Serious adverse events	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	INV_MMR Group	COM_MMR Group
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 1239 (1.69%)	28 / 1232 (2.27%)	28 / 1243 (2.25%)	77 / 3714 (2.07%)	25 / 1289 (1.94%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Burns second degree
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Foot fracture
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Head injury
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Finger amputation
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	5 / 1289 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Milk allergy
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	0 / 1239 (0.00%)	3 / 1232 (0.24%)	0 / 1243 (0.00%)	3 / 3714 (0.08%)	3 / 1289 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	3 / 1239 (0.24%)	2 / 1232 (0.16%)	3 / 1243 (0.24%)	8 / 3714 (0.22%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 3	0 / 8	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Escherichia urinary tract infection
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	2 / 1243 (0.16%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 2	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Herpangina
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Mycoplasma infection
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Nasopharyngitis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Neutropenic infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	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
Otitis media
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	4 / 1243 (0.32%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	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
Pharyngitis
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	3 / 1243 (0.24%)	6 / 3714 (0.16%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Rotavirus infection
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	3 / 1289 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral pharyngitis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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
Viral upper respiratory tract infection
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	3 / 1243 (0.24%)	5 / 3714 (0.13%)	3 / 1289 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences causally related to treatment / all	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
Type 1 diabetes mellitus
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	INV_MMR_L1 Group	INV_MMR_L2 Group	INV_MMR_L3 Group	INV_MMR Group	COM_MMR Group
Total subjects affected by non serious adverse events
subjects affected / exposed	1089 / 1239 (87.89%)	1053 / 1232 (85.47%)	1090 / 1243 (87.69%)	3232 / 3714 (87.02%)	1138 / 1289 (88.29%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Vascular disorders
Haematoma
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Pallor
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Pregnancy, puerperium and perinatal conditions
Cephalhaematoma
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
General disorders and administration site conditions
Crying
subjects affected / exposed	4 / 1239 (0.32%)	5 / 1232 (0.41%)	2 / 1243 (0.16%)	11 / 3714 (0.30%)	4 / 1289 (0.31%)
occurrences all number	4	7	2	13	5
Cyst
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	2	0	0	2	0
Discomfort
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Feeling hot
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	1	0	1	1
Influenza like illness
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Injection site bruising
subjects affected / exposed	4 / 1239 (0.32%)	5 / 1232 (0.41%)	1 / 1243 (0.08%)	10 / 3714 (0.27%)	2 / 1289 (0.16%)
occurrences all number	4	5	1	10	2
Injection site erosion
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Injection site erythema
subjects affected / exposed	321 / 1239 (25.91%)	294 / 1232 (23.86%)	328 / 1243 (26.39%)	943 / 3714 (25.39%)	335 / 1289 (25.99%)
occurrences all number	331	303	334	968	341
Injection site haematoma
subjects affected / exposed	5 / 1239 (0.40%)	1 / 1232 (0.08%)	3 / 1243 (0.24%)	9 / 3714 (0.24%)	0 / 1289 (0.00%)
occurrences all number	6	1	3	10	0
Injection site haemorrhage
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	0	1	1	2	2
Injection site induration
subjects affected / exposed	3 / 1239 (0.24%)	3 / 1232 (0.24%)	2 / 1243 (0.16%)	8 / 3714 (0.22%)	3 / 1289 (0.23%)
occurrences all number	3	3	2	8	3
Injection site mass
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	0	2	1	3	0
Injection site nodule
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Injection site pain
subjects affected / exposed	335 / 1239 (27.04%)	316 / 1232 (25.65%)	275 / 1243 (22.12%)	926 / 3714 (24.93%)	352 / 1289 (27.31%)
occurrences all number	336	317	277	930	352
Injection site papule
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	5 / 1289 (0.39%)
occurrences all number	2	2	1	5	5
Injection site swelling
subjects affected / exposed	127 / 1239 (10.25%)	106 / 1232 (8.60%)	113 / 1243 (9.09%)	346 / 3714 (9.32%)	139 / 1289 (10.78%)
occurrences all number	128	107	115	350	142
Injection site vesicles
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	1	0	1	1
Oedema peripheral
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Pain
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	1	0	1	2	2
Pyrexia
subjects affected / exposed	405 / 1239 (32.69%)	422 / 1232 (34.25%)	419 / 1243 (33.71%)	1246 / 3714 (33.55%)	412 / 1289 (31.96%)
occurrences all number	406	423	419	1248	412
Secretion discharge
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Swelling
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Vessel puncture site haematoma
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	1	1	2	0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	1	0	2	0
Drug hypersensitivity
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	0	0	2	2	1
Food allergy
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	5 / 1243 (0.40%)	9 / 3714 (0.24%)	4 / 1289 (0.31%)
occurrences all number	2	2	6	10	4
Hypersensitivity
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences all number	2	1	1	4	2
Immunisation reaction
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Milk allergy
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Seasonal allergy
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	1 / 1289 (0.08%)
occurrences all number	2	2	0	4	1
Social circumstances
Diet noncompliance
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Reproductive system and breast disorders
Acquired phimosis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Balanoposthitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	3 / 3714 (0.08%)	1 / 1289 (0.08%)
occurrences all number	1	0	2	3	1
Bilateral breast buds
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Genital labial adhesions
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	2	0	0	2	0
Vaginal mucosal blistering
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	3 / 3714 (0.08%)	4 / 1289 (0.31%)
occurrences all number	1	0	2	3	5
Bronchial hyperreactivity
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	3 / 3714 (0.08%)	2 / 1289 (0.16%)
occurrences all number	1	0	2	3	2
Bronchospasm
subjects affected / exposed	1 / 1239 (0.08%)	3 / 1232 (0.24%)	3 / 1243 (0.24%)	7 / 3714 (0.19%)	2 / 1289 (0.16%)
occurrences all number	1	3	3	7	2
Catarrh
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	3 / 3714 (0.08%)	2 / 1289 (0.16%)
occurrences all number	2	1	0	3	2
Cough
subjects affected / exposed	33 / 1239 (2.66%)	42 / 1232 (3.41%)	38 / 1243 (3.06%)	113 / 3714 (3.04%)	36 / 1289 (2.79%)
occurrences all number	36	42	38	116	38
Dyspnoea
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	2 / 1243 (0.16%)	3 / 3714 (0.08%)	2 / 1289 (0.16%)
occurrences all number	0	1	2	3	2
Epistaxis
subjects affected / exposed	2 / 1239 (0.16%)	4 / 1232 (0.32%)	1 / 1243 (0.08%)	7 / 3714 (0.19%)	2 / 1289 (0.16%)
occurrences all number	2	4	1	7	2
Nasal congestion
subjects affected / exposed	10 / 1239 (0.81%)	11 / 1232 (0.89%)	5 / 1243 (0.40%)	26 / 3714 (0.70%)	11 / 1289 (0.85%)
occurrences all number	10	12	5	27	11
Nasal discomfort
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	1	1	0	2	1
Rales
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Respiratory disorder
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	4 / 1243 (0.32%)	6 / 3714 (0.16%)	1 / 1289 (0.08%)
occurrences all number	2	0	4	6	1
Respiratory distress
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Respiratory tract congestion
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	1	2	0
Rhinitis allergic
subjects affected / exposed	3 / 1239 (0.24%)	2 / 1232 (0.16%)	3 / 1243 (0.24%)	8 / 3714 (0.22%)	1 / 1289 (0.08%)
occurrences all number	3	2	3	8	1
Rhinorrhoea
subjects affected / exposed	22 / 1239 (1.78%)	23 / 1232 (1.87%)	20 / 1243 (1.61%)	65 / 3714 (1.75%)	21 / 1289 (1.63%)
occurrences all number	23	26	21	70	22
Sinus congestion
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	2	3	0
Sneezing
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	1	0	0	1	1
Tonsillar hypertrophy
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Upper respiratory tract congestion
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Wheezing
subjects affected / exposed	2 / 1239 (0.16%)	6 / 1232 (0.49%)	6 / 1243 (0.48%)	14 / 3714 (0.38%)	1 / 1289 (0.08%)
occurrences all number	3	6	6	15	1
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Depressed mood
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Insomnia
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	1 / 1289 (0.08%)
occurrences all number	2	1	1	4	1
Irritability
subjects affected / exposed	765 / 1239 (61.74%)	730 / 1232 (59.25%)	768 / 1243 (61.79%)	2263 / 3714 (60.93%)	822 / 1289 (63.77%)
occurrences all number	775	741	775	2291	838
Middle insomnia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Restlessness
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	2 / 1289 (0.16%)
occurrences all number	0	0	1	1	2
Sleep disorder
subjects affected / exposed	3 / 1239 (0.24%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	3	0	0	3	0
Sleep terror
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Tearfulness
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	2	0	2	0
Terminal insomnia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Investigations
Cardiac murmur
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Cold agglutinins positive
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Otic examination normal
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Weight decreased
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Animal bite
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	0	2	2	0
Arthropod bite
subjects affected / exposed	7 / 1239 (0.56%)	7 / 1232 (0.57%)	5 / 1243 (0.40%)	19 / 3714 (0.51%)	4 / 1289 (0.31%)
occurrences all number	7	7	5	19	4
Arthropod sting
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	0	3	3	0
Bite
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Chemical poisoning
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Clavicle fracture
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Concussion
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Contusion
subjects affected / exposed	4 / 1239 (0.32%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	4 / 1289 (0.31%)
occurrences all number	4	0	1	5	4
Corneal abrasion
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Craniocerebral injury
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	2 / 1289 (0.16%)
occurrences all number	0	0	1	1	2
Ear canal injury
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Ear injury
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Eye contusion
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Face injury
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Fall
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	0	2	0	2	1
Foreign body in gastrointestinal tract
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	0	2	2	0
Gingival injury
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Hand fracture
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	1	0	2	0
Head injury
subjects affected / exposed	5 / 1239 (0.40%)	6 / 1232 (0.49%)	6 / 1243 (0.48%)	17 / 3714 (0.46%)	2 / 1289 (0.16%)
occurrences all number	5	6	6	17	2
Heat stroke
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Laceration
subjects affected / exposed	5 / 1239 (0.40%)	0 / 1232 (0.00%)	2 / 1243 (0.16%)	7 / 3714 (0.19%)	2 / 1289 (0.16%)
occurrences all number	5	0	2	7	2
Limb injury
subjects affected / exposed	3 / 1239 (0.24%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences all number	3	1	0	4	2
Lip injury
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	2	1	0	3	0
Nail avulsion
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Radial head dislocation
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	2	0	0	2	0
Road traffic accident
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	1	0	0	1	1
Scratch
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	0	2	1	3	0
Superficial injury of eye
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Thermal burn
subjects affected / exposed	0 / 1239 (0.00%)	3 / 1232 (0.24%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	1 / 1289 (0.08%)
occurrences all number	0	3	1	4	1
Tibia fracture
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Tongue injury
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	1	0	2	0
Upper limb fracture
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Wound
subjects affected / exposed	1 / 1239 (0.08%)	3 / 1232 (0.24%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	1 / 1289 (0.08%)
occurrences all number	1	3	1	5	1
Nervous system disorders
Drooling
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Exaggerated startle response
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Febrile convulsion
subjects affected / exposed	4 / 1239 (0.32%)	1 / 1232 (0.08%)	5 / 1243 (0.40%)	10 / 3714 (0.27%)	3 / 1289 (0.23%)
occurrences all number	4	1	5	10	3
Gross motor delay
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Headache
subjects affected / exposed	4 / 1239 (0.32%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	1 / 1289 (0.08%)
occurrences all number	4	0	1	5	1
Lethargy
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Nystagmus
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Poor quality sleep
subjects affected / exposed	4 / 1239 (0.32%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	1 / 1289 (0.08%)
occurrences all number	5	0	1	6	1
Post-traumatic headache
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Somnolence
subjects affected / exposed	534 / 1239 (43.10%)	535 / 1232 (43.43%)	533 / 1243 (42.88%)	1602 / 3714 (43.13%)	586 / 1289 (45.46%)
occurrences all number	534	535	533	1602	586
Speech disorder developmental
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Tremor
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	4 / 1243 (0.32%)	6 / 3714 (0.16%)	0 / 1289 (0.00%)
occurrences all number	0	2	4	6	0
Iron deficiency anaemia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Leukopenia
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Lymphadenitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	1	0	0	1	1
Lymphadenopathy
subjects affected / exposed	5 / 1239 (0.40%)	5 / 1232 (0.41%)	2 / 1243 (0.16%)	12 / 3714 (0.32%)	4 / 1289 (0.31%)
occurrences all number	5	5	2	12	4
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Deafness
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Ear pain
subjects affected / exposed	3 / 1239 (0.24%)	3 / 1232 (0.24%)	4 / 1243 (0.32%)	10 / 3714 (0.27%)	4 / 1289 (0.31%)
occurrences all number	3	3	4	10	4
Ear swelling
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Eustachian tube dysfunction
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Excessive cerumen production
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Otorrhoea
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	2	0	2	0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	1	1	2	0
Dacryostenosis acquired
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	1	1	1	3	0
Eye discharge
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	0	2	1	3	0
Eye inflammation
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Eye irritation
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Eye swelling
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Eyelid oedema
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	2	0	0	2	1
Hypermetropia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Lacrimation increased
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Lid sulcus deepened
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Strabismus
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	1	0	1	1
Abdominal pain
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Abdominal pain upper
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	4 / 1289 (0.31%)
occurrences all number	1	0	0	1	6
Anal fissure
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Aphthous ulcer
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	2 / 1289 (0.16%)
occurrences all number	0	0	0	0	2
Chapped lips
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Constipation
subjects affected / exposed	5 / 1239 (0.40%)	2 / 1232 (0.16%)	9 / 1243 (0.72%)	16 / 3714 (0.43%)	8 / 1289 (0.62%)
occurrences all number	5	2	9	16	8
Diarrhoea
subjects affected / exposed	64 / 1239 (5.17%)	58 / 1232 (4.71%)	49 / 1243 (3.94%)	171 / 3714 (4.60%)	64 / 1289 (4.97%)
occurrences all number	71	63	55	189	68
Dyspepsia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	2 / 1289 (0.16%)
occurrences all number	0	0	0	0	2
Dysphagia
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Faeces soft
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	1	1	2	0
Flatulence
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	1 / 1289 (0.08%)
occurrences all number	2	2	1	5	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 1239 (0.08%)	3 / 1232 (0.24%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	3 / 1289 (0.23%)
occurrences all number	1	3	0	4	3
Gingival hypertrophy
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Gingival pain
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	1	2	0
Gingival swelling
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	0	2	0	2	1
Haematochezia
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Lip swelling
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Nausea
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	1 / 1289 (0.08%)
occurrences all number	1	1	1	3	1
Oral contusion
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	2 / 1289 (0.16%)
occurrences all number	0	0	0	0	2
Oral mucosal eruption
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Post-tussive vomiting
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Ranula
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Regurgitation
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	2
Salivary gland enlargement
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	1	1	2	0
Salivary gland pain
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Salivary hypersecretion
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	2
Stomatitis
subjects affected / exposed	0 / 1239 (0.00%)	4 / 1232 (0.32%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	1 / 1289 (0.08%)
occurrences all number	0	4	1	5	1
Teething
subjects affected / exposed	91 / 1239 (7.34%)	92 / 1232 (7.47%)	77 / 1243 (6.19%)	260 / 3714 (7.00%)	95 / 1289 (7.37%)
occurrences all number	114	106	92	312	114
Toothache
subjects affected / exposed	4 / 1239 (0.32%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	6 / 1289 (0.47%)
occurrences all number	6	0	1	7	7
Vomiting
subjects affected / exposed	38 / 1239 (3.07%)	35 / 1232 (2.84%)	34 / 1243 (2.74%)	107 / 3714 (2.88%)	43 / 1289 (3.34%)
occurrences all number	39	38	38	115	46
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Blister
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	2	2	0
Dermatitis
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences all number	1	2	1	4	2
Dermatitis allergic
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Dermatitis atopic
subjects affected / exposed	2 / 1239 (0.16%)	3 / 1232 (0.24%)	4 / 1243 (0.32%)	9 / 3714 (0.24%)	3 / 1289 (0.23%)
occurrences all number	2	3	4	9	3
Dermatitis contact
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	2 / 1243 (0.16%)	5 / 3714 (0.13%)	0 / 1289 (0.00%)
occurrences all number	1	2	2	5	0
Dermatitis diaper
subjects affected / exposed	3 / 1239 (0.24%)	4 / 1232 (0.32%)	3 / 1243 (0.24%)	10 / 3714 (0.27%)	5 / 1289 (0.39%)
occurrences all number	4	4	4	12	5
Drug eruption
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Dry skin
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Eczema
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	2 / 1243 (0.16%)	4 / 3714 (0.11%)	5 / 1289 (0.39%)
occurrences all number	0	2	2	4	5
Eczema nummular
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Erythema
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	1 / 1289 (0.08%)
occurrences all number	2	1	1	4	1
Hyperhidrosis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Hyperkeratosis
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Ingrowing nail
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Keratosis pilaris
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Macule
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Miliaria
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Papule
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Prurigo
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	2	0	0	2	0
Pruritus
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Rash
subjects affected / exposed	352 / 1239 (28.41%)	331 / 1232 (26.87%)	360 / 1243 (28.96%)	1043 / 3714 (28.08%)	378 / 1289 (29.33%)
occurrences all number	352	331	360	1043	378
Seborrhoea
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Skin irritation
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	2	0	0	2	2
Skin mass
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Skin warm
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	1 / 1289 (0.08%)
occurrences all number	1	1	1	3	1
Solar dermatitis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Swelling face
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	0	1	1	2	1
Urticaria
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	0 / 1289 (0.00%)
occurrences all number	4	1	1	6	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Polyuria
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Urinary tract disorder
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Elbow deformity
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Knee deformity
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Synovial cyst
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Acute sinusitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	1	2	0
Adenovirus infection
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	1	1	0	2	1
Beta haemolytic streptococcal infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Body tinea
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Bronchiolitis
subjects affected / exposed	2 / 1239 (0.16%)	7 / 1232 (0.57%)	7 / 1243 (0.56%)	16 / 3714 (0.43%)	6 / 1289 (0.47%)
occurrences all number	2	7	7	16	6
Bronchitis
subjects affected / exposed	10 / 1239 (0.81%)	12 / 1232 (0.97%)	10 / 1243 (0.80%)	32 / 3714 (0.86%)	12 / 1289 (0.93%)
occurrences all number	10	13	11	34	13
Bullous impetigo
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Candida infection
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences all number	1	3	1	5	2
Candida nappy rash
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Cellulitis
subjects affected / exposed	2 / 1239 (0.16%)	0 / 1232 (0.00%)	3 / 1243 (0.24%)	5 / 3714 (0.13%)	0 / 1289 (0.00%)
occurrences all number	2	0	3	5	0
Clostridium difficile infection
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Conjunctivitis
subjects affected / exposed	26 / 1239 (2.10%)	21 / 1232 (1.70%)	39 / 1243 (3.14%)	86 / 3714 (2.32%)	32 / 1289 (2.48%)
occurrences all number	26	21	41	88	33
Conjunctivitis bacterial
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	0	1	1	2	0
Coxsackie viral infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Croup infectious
subjects affected / exposed	4 / 1239 (0.32%)	11 / 1232 (0.89%)	8 / 1243 (0.64%)	23 / 3714 (0.62%)	6 / 1289 (0.47%)
occurrences all number	4	11	8	23	6
Ear infection
subjects affected / exposed	9 / 1239 (0.73%)	14 / 1232 (1.14%)	4 / 1243 (0.32%)	27 / 3714 (0.73%)	13 / 1289 (1.01%)
occurrences all number	9	14	4	27	13
Enterovirus infection
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	3 / 3714 (0.08%)	2 / 1289 (0.16%)
occurrences all number	1	2	0	3	2
Epstein-barr virus infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Exanthema subitum
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	2 / 1289 (0.16%)
occurrences all number	0	0	0	0	2
Eye infection
subjects affected / exposed	1 / 1239 (0.08%)	3 / 1232 (0.24%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	4 / 1289 (0.31%)
occurrences all number	1	3	1	5	4
Folliculitis
subjects affected / exposed	0 / 1239 (0.00%)	3 / 1232 (0.24%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	0 / 1289 (0.00%)
occurrences all number	0	3	1	4	0
Fungal infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Gastroenteritis
subjects affected / exposed	27 / 1239 (2.18%)	21 / 1232 (1.70%)	35 / 1243 (2.82%)	83 / 3714 (2.23%)	31 / 1289 (2.40%)
occurrences all number	28	21	38	87	32
Gastroenteritis norovirus
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Gastroenteritis rotavirus
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	3 / 1239 (0.24%)	6 / 1232 (0.49%)	6 / 1243 (0.48%)	15 / 3714 (0.40%)	6 / 1289 (0.47%)
occurrences all number	3	6	6	15	6
Gastrointestinal infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Gingivitis
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	1	1	1	3	0
Hand-foot-and-mouth disease
subjects affected / exposed	2 / 1239 (0.16%)	3 / 1232 (0.24%)	9 / 1243 (0.72%)	14 / 3714 (0.38%)	5 / 1289 (0.39%)
occurrences all number	2	3	9	14	5
Herpangina
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	0	1	1	2	2
Herpes simplex
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Hordeolum
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	1	1	0	2	1
Impetigo
subjects affected / exposed	4 / 1239 (0.32%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	6 / 3714 (0.16%)	2 / 1289 (0.16%)
occurrences all number	4	1	1	6	2
Infected bite
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Influenza
subjects affected / exposed	2 / 1239 (0.16%)	5 / 1232 (0.41%)	1 / 1243 (0.08%)	8 / 3714 (0.22%)	10 / 1289 (0.78%)
occurrences all number	2	5	1	8	12
Injection site abscess
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Laryngitis
subjects affected / exposed	1 / 1239 (0.08%)	7 / 1232 (0.57%)	2 / 1243 (0.16%)	10 / 3714 (0.27%)	6 / 1289 (0.47%)
occurrences all number	1	9	2	12	6
Lice infestation
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Localised infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Lower respiratory tract infection
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	1	0	1	2	2
Molluscum contagiosum
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	0 / 1289 (0.00%)
occurrences all number	1	1	1	3	0
Nasopharyngitis
subjects affected / exposed	74 / 1239 (5.97%)	75 / 1232 (6.09%)	74 / 1243 (5.95%)	223 / 3714 (6.00%)	65 / 1289 (5.04%)
occurrences all number	83	82	82	247	68
Oral candidiasis
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	5 / 3714 (0.13%)	0 / 1289 (0.00%)
occurrences all number	2	2	1	5	0
Oral herpes
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	2 / 1289 (0.16%)
occurrences all number	0	1	1	2	2
Oral infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Otitis externa
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	0	0	1	1	1
Otitis media
subjects affected / exposed	80 / 1239 (6.46%)	75 / 1232 (6.09%)	62 / 1243 (4.99%)	217 / 3714 (5.84%)	86 / 1289 (6.67%)
occurrences all number	86	79	67	232	89
Otitis media acute
subjects affected / exposed	8 / 1239 (0.65%)	7 / 1232 (0.57%)	13 / 1243 (1.05%)	28 / 3714 (0.75%)	9 / 1289 (0.70%)
occurrences all number	10	7	14	31	9
Otitis media chronic
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Paronychia
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Periorbital cellulitis
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	1	0	0	1	1
Pharyngitis
subjects affected / exposed	20 / 1239 (1.61%)	30 / 1232 (2.44%)	14 / 1243 (1.13%)	64 / 3714 (1.72%)	23 / 1289 (1.78%)
occurrences all number	20	30	14	64	24
Pharyngitis streptococcal
subjects affected / exposed	0 / 1239 (0.00%)	3 / 1232 (0.24%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	0 / 1289 (0.00%)
occurrences all number	0	3	1	4	0
Pharyngotonsillitis
subjects affected / exposed	2 / 1239 (0.16%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	2 / 1289 (0.16%)
occurrences all number	2	1	1	4	2
Pneumonia
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	5 / 1243 (0.40%)	7 / 3714 (0.19%)	1 / 1289 (0.08%)
occurrences all number	1	1	5	7	1
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Respiratory syncytial virus infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	8 / 1239 (0.65%)	11 / 1232 (0.89%)	9 / 1243 (0.72%)	28 / 3714 (0.75%)	7 / 1289 (0.54%)
occurrences all number	8	12	11	31	9
Respiratory tract infection viral
subjects affected / exposed	3 / 1239 (0.24%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	4 / 1289 (0.31%)
occurrences all number	3	1	0	4	4
Rhinitis
subjects affected / exposed	46 / 1239 (3.71%)	49 / 1232 (3.98%)	38 / 1243 (3.06%)	133 / 3714 (3.58%)	41 / 1289 (3.18%)
occurrences all number	50	55	42	147	44
Roseola
subjects affected / exposed	1 / 1239 (0.08%)	2 / 1232 (0.16%)	1 / 1243 (0.08%)	4 / 3714 (0.11%)	0 / 1289 (0.00%)
occurrences all number	1	2	1	4	0
Salmonellosis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Scarlet fever
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	1	2	0
Sinusitis
subjects affected / exposed	9 / 1239 (0.73%)	3 / 1232 (0.24%)	4 / 1243 (0.32%)	16 / 3714 (0.43%)	3 / 1289 (0.23%)
occurrences all number	10	3	4	17	3
Skin bacterial infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0
Skin candida
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	0	1	2	0
Staphylococcal infection
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Streptococcal infection
subjects affected / exposed	0 / 1239 (0.00%)	2 / 1232 (0.16%)	3 / 1243 (0.24%)	5 / 3714 (0.13%)	3 / 1289 (0.23%)
occurrences all number	0	2	3	5	3
Subcutaneous abscess
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	1	0	0	1	0
Tonsillitis
subjects affected / exposed	21 / 1239 (1.69%)	9 / 1232 (0.73%)	9 / 1243 (0.72%)	39 / 3714 (1.05%)	15 / 1289 (1.16%)
occurrences all number	22	10	11	43	16
Tooth abscess
subjects affected / exposed	0 / 1239 (0.00%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	1	0	1	0
Upper respiratory tract infection
subjects affected / exposed	106 / 1239 (8.56%)	124 / 1232 (10.06%)	122 / 1243 (9.81%)	352 / 3714 (9.48%)	122 / 1289 (9.46%)
occurrences all number	117	132	132	381	129
Urinary tract infection
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	1 / 1243 (0.08%)	3 / 3714 (0.08%)	2 / 1289 (0.16%)
occurrences all number	2	1	1	4	2
Viral diarrhoea
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	2 / 3714 (0.05%)	1 / 1289 (0.08%)
occurrences all number	1	0	1	2	1
Viral infection
subjects affected / exposed	15 / 1239 (1.21%)	21 / 1232 (1.70%)	23 / 1243 (1.85%)	59 / 3714 (1.59%)	15 / 1289 (1.16%)
occurrences all number	15	22	26	63	15
Viral pharyngitis
subjects affected / exposed	2 / 1239 (0.16%)	2 / 1232 (0.16%)	0 / 1243 (0.00%)	4 / 3714 (0.11%)	1 / 1289 (0.08%)
occurrences all number	2	2	0	4	1
Viral rash
subjects affected / exposed	1 / 1239 (0.08%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	1 / 3714 (0.03%)	1 / 1289 (0.08%)
occurrences all number	1	0	0	1	1
Viral tonsillitis
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	3 / 1239 (0.24%)	3 / 1232 (0.24%)	4 / 1243 (0.32%)	10 / 3714 (0.27%)	3 / 1289 (0.23%)
occurrences all number	3	3	4	10	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	547 / 1239 (44.15%)	537 / 1232 (43.59%)	526 / 1243 (42.32%)	1610 / 3714 (43.35%)	549 / 1289 (42.59%)
occurrences all number	548	538	528	1614	550
Dehydration
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	0 / 1243 (0.00%)	0 / 3714 (0.00%)	1 / 1289 (0.08%)
occurrences all number	0	0	0	0	1
Lactose intolerance
subjects affected / exposed	1 / 1239 (0.08%)	1 / 1232 (0.08%)	0 / 1243 (0.00%)	2 / 3714 (0.05%)	0 / 1289 (0.00%)
occurrences all number	1	1	0	2	0
Polydipsia
subjects affected / exposed	0 / 1239 (0.00%)	0 / 1232 (0.00%)	1 / 1243 (0.08%)	1 / 3714 (0.03%)	0 / 1289 (0.00%)
occurrences all number	0	0	1	1	0

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value

Primary: Anti-measles virus antibody concentrations

Primary: Anti-measles virus antibody concentrations

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value

Primary: Anti-mumps virus antibody concentration

Primary: Anti-mumps virus antibody concentration

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value

Primary: Anti-rubella virus antibody concentration

Primary: Anti-rubella virus antibody concentration

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Anti-measles virus antibody concentrations in pooled MMR groups

Primary: Anti-measles virus antibody concentrations in pooled MMR groups

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Anti-mumps virus antibody concentration in pooled MMR groups

Primary: Anti-mumps virus antibody concentration in pooled MMR groups

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value in pooled MMR groups

Primary: Anti-rubella virus antibody concentration in pooled MMR groups

Primary: Anti-rubella virus antibody concentration in pooled MMR groups

Secondary: Percentage of subjects with an anti-Varicella Zoster Virus (VZV) antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

Secondary: Percentage of subjects with an anti-Varicella Zoster Virus (VZV) antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

Secondary: Anti-VZV virus antibody concentration in US sub-cohort of pooled MMR groups

Secondary: Anti-VZV virus antibody concentration in US sub-cohort of pooled MMR groups

Secondary: Percentage of subjects with an anti-HAV antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

Secondary: Percentage of subjects with an anti-HAV antibody concentration equal to or above the cut-off value in US sub-cohort of pooled MMR groups

Secondary: Anti-HAV antibody concentrations in US sub-cohort of pooled MMR groups

Secondary: Anti-HAV antibody concentrations in US sub-cohort of pooled MMR groups

Secondary: Anti-S.pneumoniae antibody concentration in US sub-cohort of pooled MMR groups

Secondary: Anti-S.pneumoniae antibody concentration in US sub-cohort of pooled MMR groups

Secondary: Number of subjects with any solicited local adverse events (AEs)

Secondary: Number of subjects with any solicited local adverse events (AEs)

Secondary: Number of subjects with any solicited general AEs

Secondary: Number of subjects with any solicited general AEs

Secondary: Number of subjects reporting any fever

Secondary: Number of subjects reporting any fever

Secondary: Number of subjects reporting any rash

Secondary: Number of subjects reporting any rash

Secondary: Number of subjects reporting any MMR specific solicited AEs

Secondary: Number of subjects reporting any MMR specific solicited AEs

Secondary: Number of subjects reporting any unsolicited AEs

Secondary: Number of subjects reporting any unsolicited AEs

Secondary: Number of subjects reporting AEs of specific interest

Secondary: Number of subjects reporting AEs of specific interest

Secondary: Number of subjects reporting any Serious adverse events (SAEs)

Secondary: Number of subjects reporting any Serious adverse events (SAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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