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Clinical Trial Results:
A Phase III, double-blind, randomized, multicenter study to assess safety and immunogenicity of GlaxoSmithKline Biologicals’ Quadrivalent Split Virion Influenza Vaccine (GSK2321138A) manufactured with a new process, in adults aged 18 to 49 years and in children aged 6 months to 17 years.

Summary
EudraCT number	2014-000955-10
Trial protocol	DE ES CZ
Global end of trial date	18 Apr 2015

Results information
Results version number	v2(current)
This version publication date	24 Dec 2017
First version publication date	20 Apr 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

201251

ISRCTN number

US NCT number

NCT02207413

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

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

Public contact

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

Scientific contact

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

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

18 Apr 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

•To describe the safety of 1 dose of FLU D-QIV vaccine produced by the IP and 1 dose of FLU D-QIV vaccine produced by the LP in terms of solicited (7 days after vaccination), unsolicited adverse events (AEs) 21 days after vaccination in subjects aged 18-49 years and Oculorespiratory Syndrome (ORS) over 3 days post vaccination in 18-49 & 3-17 years of age •To demonstrate the immunogenic non-inferiority of FLU D-QIV IP as compared to FLU D-QIV LP in terms of haemagglutination inhibition (HI) geometric mean titer (GMT) ratio at 28 days after completion of the vaccination series in subjects aged 3-17 years. •To demonstrate the immunogenic non-inferiority of FLU D-QIV IP as compared to FLU D-QIV LP in terms of HI GMT ratio at 28 days after completion of the vaccination series in subjects aged 6-35 months. •To demonstrate there is no significant increase of fever ≥38ºC after any dose with FLU D-QIV IP compared to FLU D-QIV LP during the 7 days post-vaccination in subjects aged 6-35 months.

Protection of trial subjects

All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed-up for 31 days after the last vaccination/product administration.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Aug 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 177

Country: Number of subjects enrolled

Spain: 455

Country: Number of subjects enrolled

Czech Republic: 174

Country: Number of subjects enrolled

France: 226

Country: Number of subjects enrolled

Germany: 537

Country: Number of subjects enrolled

United States: 138

Country: Number of subjects enrolled

Bangladesh: 179

Worldwide total number of subjects

1886

EEA total number of subjects

1569

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)

623

Children (2-11 years)

849

Adolescents (12-17 years)

287

Adults (18-64 years)

127

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Primed subjects: Received 2 doses of seasonal influenza vaccine separated by at least one month during the last season or had received at least 1 dose prior to last season. Unprimed subjects: Did not receive any seasonal influenza vaccine in the past or received only 1 dose for the first time in the last influenza season.

Screening details

For 5 subjects, study vaccine dose not administered at all but subject number was allocated. Some data has been analysed in sub-groups by age: 3-4 years, 5-17 years, 6 months to <5 years.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

By double-blind, it was meant that during the course of the study, the subject, subject ‘s parent(s)/LAR(s), investigator and sponsor staff who were involved in the treatment or clinical evaluation of the subjects and review/analysis of data were unaware of the treatment assignments. The laboratory in charge of the laboratory testing was blinded to the treatment, and codes were used to link the subject and study to each sample.

Are arms mutually exclusive

Yes

Influsplit Tetra_IP Adult Group

Arm description

Subjects in the Influsplit Tetra_IP group aged between 18 to 49 years received 1 dose of Influsplit Tetra™ vaccine produced by investigational process (IP) at Day 0. Influsplit Tetra™ vaccine produced by IP was administered intramuscularly in the deltoid region of left or non-dominant arm.

Arm type

Experimental

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by investigational process (IP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Influsplit Tetra™ vaccine using a new manufacturing process administered intramuscularly (IM) in the deltoid region of non-dominant arm (Dose 1) in Adults Group and in non-dominant deltoid or left anterolateral thigh (Dose 1) and dominant deltoid or right anterolateral (Dose 2 – unprimed subjects) in 6-35m and 3-17y Groups.

Influsplit Tetra_LP Adult Group

Arm description

Subjects in the Influsplit Tetra_LP aged between 18 to 49 years received 1 dose of Influsplit Tetra™ vaccine produced by currently licensed process (LP) at Day 0. Influsplit Tetra™ vaccine produced by currently LP was administered intramuscularly in the deltoid region of left or non-dominant arm.

Arm type

Active comparator

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by licensed process (LP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Influsplit Tetra™ vaccine using a licensed manufacturing process administered IM in the deltoid region of non-dominant arm (Dose 1) in Adults Group and in non-dominant deltoid or left anterolateral thigh (Dose 1) and dominant deltoid or right anterolateral (Dose 2 – unprimed subjects) in 6-35m and 3-17y Groups.

Influsplit Tetra_IP 3-17y Group

Arm description

Subjects in the Influsplit Tetra_IP group aged between 3 years to <9 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by investigational process (IP). Subjects aged 9-17 years received only 1 dose of Influsplit Tetra™ vaccine produced by IP at Day 0. Influsplit Tetra™ vaccine produced by IP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Arm type

Experimental

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by investigational process (IP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Influsplit Tetra_LP 3-17y Group

Arm description

Subjects in the Influsplit Tetra_LP group aged between 3 years to <9 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by licensed process (LP). Subjects aged 9-17 years received only 1 dose of Influsplit Tetra™ vaccine produced by LP at Day 0. Influsplit Tetra™ vaccine produced by LP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Arm type

Active comparator

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by licensed process (LP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Influsplit Tetra_IP 6-35m Group

Arm description

Subjects in the Influsplit Tetra_IP group aged between 6 months to 35 months received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by investigational process (IP). Influsplit Tetra™ vaccine produced by IP was administered intramuscularly the anterolateral region of left thigh for subjects below 12 months of age and in the deltoid region of left or non-dominant arm in subjects ≥ 12 months of age (Day 0) and in the anterolateral region of right thigh for subjects below 12 months of age and in the deltoid region of right or dominant arm in subjects ≥ 12 months of age (Day 28).

Arm type

Experimental

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by investigational process (IP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Influsplit Tetra_LP 6-35m Group

Arm description

Subjects in the Influsplit Tetra_LP group aged between 6 months to 35 months received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by licensed process (LP). Influsplit Tetra™ vaccine produced by LP was administered intramuscularly the anterolateral region of left thigh for subjects below 12 months of age and in the deltoid region of left or non-dominant arm in subjects ≥ 12 months of age (Day 0) and in the anterolateral region of right thigh for subjects below 12 months of age and in the deltoid region of right or dominant arm in subjects ≥ 12 months of age (Day 28).

Arm type

Active comparator

Investigational medicinal product name

Influsplit Tetra™ vaccine produced by licensed process (LP)

Investigational medicinal product code

Other name

Fluarix Tetra™, Fluarix Quadrivalent® (GSK2321138A)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Number of subjects in period 1 ^[1]	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Started	60	60	410	411	466	474
Completed	59	60	410	410	459	461
Not completed	1	0	0	1	7	13
Consent withdrawn by subject	1	-	-	-	3	7
Adverse event, non-fatal	-	-	-	-	2	1
Migrated/moved from study area	-	-	-	-	1	-
Lost to follow-up	-	-	-	1	1	5

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: For 5 subjects, study vaccine dose not administered at all but subject number was allocated. Some data has been analysed in sub-groups by age: 3-4 years, 5-17 years, 6 months to less than 5 years.

Baseline characteristics

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Reporting group title

Influsplit Tetra_IP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_LP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_IP 3-17y Group

Reporting group description

Reporting group title

Influsplit Tetra_LP 3-17y Group

Reporting group description

Reporting group title

Influsplit Tetra_IP 6-35m Group

Reporting group description

Reporting group title

Influsplit Tetra_LP 6-35m Group

Reporting group description

Reporting group values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group	Total
Number of subjects	60	60	410	411	466	474
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	29.8 ± 8.7	31.2 ± 9.3	9.4 ± 4.2	9.4 ± 4.2	99 ± 99	99 ± 99	-
Gender categorical
Units: Subjects
Female	41	35	196	187	223	209	891
Male	19	25	214	224	243	265	990
Age Continuous -
Units: Months
arithmetic mean (standard deviation)	99 ± 99	99 ± 99	99 ± 99	99 ± 99	19.7 ± 8.0	19.9 ± 8.3	-

Subject analysis set title

influsplit tetra_ip 3-4y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_IP group aged between 3 to 4 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by investigational process (IP). Influsplit Tetra™ vaccine produced by IP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Subject analysis set title

influsplit tetra_lp 3-4y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_LP group aged between 3 to 4 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by licensed process (LP). Influsplit Tetra™ vaccine produced by LP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Subject analysis set title

influsplit tetra_ip 5-17y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_IP group aged between 5 years to <9 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by investigational process (IP). Subjects aged 9-17 years received only 1 dose of Influsplit Tetra™ vaccine produced by IP at Day 0. Influsplit Tetra™ vaccine produced by IP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Subject analysis set title

influsplit tetra_lp 5-17y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_LP group aged between 5 years to <9 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by licensed process (LP). Subjects aged 9-17 years received only 1 dose of Influsplit Tetra™ vaccine produced by LP at Day 0. Influsplit Tetra™ vaccine produced by LP was administered intramuscularly in the deltoid region of left or non-dominant arm (Day 0) and in the deltoid region of right or dominant arm (Day 28).

Subject analysis set title

influsplit tetra_ip 6m-<5y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_IP group aged between 6 months to <5 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by investigational process (IP). Influsplit Tetra™ vaccine produced by IP was administered intramuscularly the anterolateral region of left thigh for subjects below 12 months of age and in the deltoid region of left or non-dominant arm in subjects ≥ 12 months of age (Day 0) and in the anterolateral region of right thigh for subjects below 12 months of age and in the deltoid region of right or dominant arm in subjects ≥ 12 months of age (Day 28).

Subject analysis set title

influsplit tetra_lp 6m-<5y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects in the Influsplit Tetra_LP group aged between 6 months to <5 years received 1 dose (primed subjects) at Day 0 and 2 doses (unprimed subjects) at Days 0 and 28 of Influsplit Tetra™ vaccine produced by licensed process (LP). Influsplit Tetra™ vaccine produced by LP was administered intramuscularly the anterolateral region of left thigh for subjects below 12 months of age and in the deltoid region of left or non-dominant arm in subjects ≥ 12 months of age (Day 0) and in the anterolateral region of right thigh for subjects below 12 months of age and in the deltoid region of right or dominant arm in subjects ≥ 12 months of age (Day 28).

Subject analysis sets values	influsplit tetra_ip 3-4y group	influsplit tetra_lp 3-4y group	influsplit tetra_ip 5-17y group	influsplit tetra_lp 5-17y group	influsplit tetra_ip 6m-<5y group	influsplit tetra_lp 6m-<5y group
Number of subjects	70	72	340	338	532	542
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	99 ± 99	99 ± 99	99 ± 99	99 ± 99	99 ± 99	99 ± 99
Gender categorical
Units: Subjects
Female
Male
Age Continuous -
Units: Months
arithmetic mean (standard deviation)	99 ± 99	99 ± 99	99 ± 99	99 ± 99	99 ± 99	99 ± 99

End points

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Reporting group title

Influsplit Tetra_IP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_LP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_IP 3-17y Group

Reporting group description

Reporting group title

Influsplit Tetra_LP 3-17y Group

Reporting group description

Reporting group title

Influsplit Tetra_IP 6-35m Group

Reporting group description

Reporting group title

Influsplit Tetra_LP 6-35m Group

Reporting group description

Subject analysis set title

influsplit tetra_ip 3-4y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

influsplit tetra_lp 3-4y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

influsplit tetra_ip 5-17y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

influsplit tetra_lp 5-17y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

influsplit tetra_ip 6m-<5y group

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

influsplit tetra_lp 6m-<5y group

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Number of subjects aged 18-49 years reporting solicited local adverse events (AEs).

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End point title

Number of subjects aged 18-49 years reporting solicited local adverse events (AEs). ^[1] ^[2]

End point description

Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = significant pain at rest and pain that prevented normal everyday activities. Grade 3 redness and swelling = greater than 100 millimeters (mm) i.e. >100mm.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	59
Units: Subjects
Any Pain	41	32
Grade 3 Pain	1	0
Any Redness	1	1
Grade 3 Redness	0	0
Any Swelling	2	4
Grade 3 Swelling	0	0

No statistical analyses for this end point

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related solicited general symptoms.

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End point title

Number of subjects aged 18-49 years reporting any, grade 3 and related solicited general symptoms. ^[3] ^[4]

End point description

Solicited general symptoms assessed were fatigue,gastrointestinal symptoms, headache, Joint Pain, myalgia, shivering and fever. Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 was defined as symptoms that prevented normal activities. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Any fever was defined as subjects with a documented temperature of greater than or equal to (≥) 38°C/100.4°F by any route and all subjects reporting temperature less than (< )38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever was defined as temperature ≥39.0°C.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	59
Units: Subjects
Any Fatigue	32	20
Grade 3 Fatigue	0	0
Related Fatigue	28	20
Any Gastrointestinal symptoms	6	6
Grade 3 Gastrointestinal symptoms	0	0
Related Gastrointestinal symptoms	4	4
Any Headache	30	16
Grade 3 Headache	1	1
Related Headache	26	14
Any Joint Pain	8	5
Grade 3 Joint Pain	0	0
Related Joint Pain	8	5
Any Myalgia	21	13
Grade 3 Myalgia	1	0
Related Myalgia	20	13
Any Shivering	9	7
Grade 3 Shivering	1	0
Related Shivering	8	6
Any Fever	2	2
Fever (≥38.0°C)	2	1
Grade 3 Fever	0	0
Related Fever	2	2
≥38.0°C Related Fever	2	1

No statistical analyses for this end point

Primary: Duration of solicited local and general AEs in subjects aged 18-49 years.

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End point title

Duration of solicited local and general AEs in subjects aged 18-49 years. ^[5] ^[6]

End point description

Duration was defined as number of days with any grade of local and general symptoms.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	41	32
Units: Days
median (full range (min-max))
Fatigue	2.0 (1.0 to 7.0)	2.0 (1.0 to 4.0)
Gastrointestinal symptoms	1.5 (1.0 to 4.0)	1.0 (1.0 to 3.0)
Headache	1.0 (1.0 to 6.0)	1.5 (1.0 to 5.0)
Joint Pain	1.0 (1.0 to 4.0)	3.0 (1.0 to 4.0)
Myalgia	2.0 (1.0 to 7.0)	2.0 (1.0 to 4.0)
Pain	2.0 (1.0 to 3.0)	2.0 (1.0 to 7.0)
Redness	2.0 (2.0 to 2.0)	1.0 (1.0 to 1.0)
Shivering	2.0 (1.0 to 4.0)	3.0 (1.0 to 5.0)
Swelling	1.5 (1.0 to 2.0)	2.5 (2.0 to 4.0)
Fever	1.0 (1.0 to 1.0)	1.5 (1.0 to 2.0)

No statistical analyses for this end point

Primary: Number of subjects aged 18-49 years reporting solicited Oculorespiratory Syndrome (ORS) like symptoms.

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End point title

Number of subjects aged 18-49 years reporting solicited Oculorespiratory Syndrome (ORS) like symptoms. ^[7] ^[8]

End point description

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any was defined as any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 ORS was defined as ORS symptoms that prevented normal activities. Related ORS was defined as ORS symptom(s) assessed by the investigator as causally related to the vaccination.

End point type

Primary

End point timeframe

During the 3-day (Days 0-2) post-vaccination period

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	59
Units: Subjects
Any Chest Tightness	0	0
Grade 3 Chest Tightness	0	0
Related Chest Tightness	0	0
Any Cough	3	2
Grade 3 Cough	0	0
Related Cough	3	1
Any Difficulty Breathing	0	0
Grade 3 Difficulty Breathing	0	0
Related Difficulty Breathing	0	0
Any Hoarseness	1	1
Grade 3 Hoarseness	0	0
Related Hoarseness	1	1
Any Red Eyes	1	1
Grade 3 Red Eyes	0	0
Related Red Eyes	1	0
Any Sore Throat	4	2
Grade 3 Sore Throat	0	0
Related Sore Throat	3	1
Any Swallowing Difficulty	3	1
Grade 3 Swallowing Difficulty	0	0
Related Swallowing Difficulty	2	0
Any Swelling of the face	0	0
Grade 3 Swelling of the face	0	0
Related Swelling of the face	0	0
Any Wheezing	0	0
Grade 3 Wheezing	0	0
Related Wheezing	0	0

No statistical analyses for this end point

Primary: Number of subjects aged 18-49 years reporting the occurrence of medically attended events (MAEs).

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End point title

Number of subjects aged 18-49 years reporting the occurrence of medically attended events (MAEs). ^[9] ^[10]

End point description

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was defined as MAE that prevented normal activities. Related was defined as MAE assessed by the investigator to be causally related to the study vaccination.

End point type

Primary

End point timeframe

During the entire study period (approximately 21 days following vaccination)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	60
Units: Subjects
Any MAE(s)	9	8
Grade 3 MAE(s)	3	1
Related MAE(s)	0	0

No statistical analyses for this end point

Primary: Number of subjects aged 3-17 years reporting solicited local adverse events (AEs).

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End point title

Number of subjects aged 3-17 years reporting solicited local adverse events (AEs). ^[11] ^[12]

End point description

Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = Cried when limb was moved/spontaneously painful. Grade 3 redness and swelling = greater than 50 millimeters (mm) i.e. >50mm.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.
[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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	410	410
Units: Subjects
Any Pain, Dose 1	243	253
Grade 3 Pain, Dose 1	14	20
Any Redness, Dose 1	118	119
Grade 3 Redness, Dose 1	8	7
Any Swelling, Dose 1	102	100
Grade 3 Swelling, Dose 1	7	7
Any Pain, Dose 2	36	39
Grade 3 Pain, Dose 2	0	2
Any Redness, Dose 2	25	21
Grade 3 Redness, Dose 2	0	0
Any Swelling, Dose 2	16	17
Grade 3 Swelling, Dose 2	1	0
Any Pain, Across Doses	252	264
Grade 3 Pain, Across Doses	14	21
Any Redness, Across Doses	129	128
Grade 3 Redness, Across Doses	8	7
Any Swelling, Across Doses	109	110
Grade 3 Swelling, Across Doses	8	7

No statistical analyses for this end point

Primary: Number of subjects aged 3-4 years reporting any, grade 3 and related solicited general symptoms.

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End point title

Number of subjects aged 3-4 years reporting any, grade 3 and related solicited general symptoms. ^[13]

End point description

Solicited general symptoms assessed were drowsiness, irritability/fussiness, loss of appetite and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Grade 3 irritability/fussiness was defined as crying that could not be comforted/prevented normal activity. Grade 3 loss of appetite was defined as not eating at all. Grade 3 drowsiness was defined as drowsiness that prevented normal activity. Any fever was defined as subjects with a documented temperature of greater than or equal to (≥) 38°C/100.4°F by any route and all subjects reporting temperature less than (< )38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever was defined as temperature greater than (>) 39.0°C.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.

End point values	influsplit tetra_ip 3-4y group	influsplit tetra_lp 3-4y group
Number of subjects analysed	70	72
Units: Subjects
Any Drowsiness, Dose 1	14	7
Grade 3 Drowsiness, Dose 1	0	1
Related Drowsiness, Dose 1	10	4
Any Irritability, Dose 1	9	12
Grade 3 Irritability, Dose 1	1	1
Related Irritability, Dose 1	6	8
Any Loss of appetite, Dose 1	9	14
Grade 3 Loss of appetite, Dose 1	2	1
Related Loss of appetite, Dose 1	6	6
Any Fever, Dose 1	5	7
Fever (≥38.0°C), Dose 1	4	7
Grade 3 Fever, Dose 1	1	3
Related Fever, Dose 1	1	5
≥38.0°C Related Fever, Dose 1	1	5
Any Drowsiness, Dose 2	5	6
Grade 3 Drowsiness, Dose 2	0	1
Related Drowsiness, Dose 2	3	4
Any Irritability, Dose 2	2	8
Grade 3 Irritability, Dose 2	0	0
Related Irritability, Dose 2	2	6
Any Loss of appetite, Dose 2	4	6
Grade 3 Loss of appetite, Dose 2	0	0
Related Loss of appetite, Dose 2	2	3
Any Fever, Dose 2	0	4
Fever (≥38.0°C), Dose 2]	0	3
Grade 3 Fever, Dose 2	0	0
Related Fever, Dose 2	0	2
≥38.0°C Related Fever, Dose 2	0	1
Any Drowsiness, Across Doses	16	11
Grade 3 Drowsiness, Across Doses	0	2
Related Drowsiness, Across Doses	10	8
Any Irritability, Across Doses	10	16
Grade 3 Irritability ,Across Doses	1	1
Related Irritability, Across Doses	7	11
Any Loss of appetite,Across Doses	13	16
Grade 3 Loss of appetite, Across Doses	2	1
Related Loss of appetite, Across Doses	8	8
Any Fever, Across Doses	5	10
Fever (≥38.0°C), Across Doses	4	9
Grade 3 Fever, Across Doses	1	3
Related Fever, Across Doses	1	6
≥38.0°C Related Fever, Across Doses	1	5

No statistical analyses for this end point

Primary: Number of subjects aged 5-17 years reporting any, grade 3 and related solicited general symptoms.

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End point title

Number of subjects aged 5-17 years reporting any, grade 3 and related solicited general symptoms. ^[14]

End point description

Solicited general symptoms assessed were fatigue, gastrointestinal symptoms, headache, joint pain, myalgia, shivering and fever (Fever = temperature above 38.0 degrees Celsius (°C)). Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever = temperature above 39.0°C.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted.

End point values	influsplit tetra_ip 5-17y group	influsplit tetra_lp 5-17y group
Number of subjects analysed	340	338
Units: Subjects
Any Fatigue, Dose 1	94	99
Grade 3 Fatigue, Dose 1	8	13
Related Fatigue, Dose 1	65	70
Any Gastrointestinal, Dose 1	35	32
Grade 3 Gastrointestinal, Dose 1	2	1
Related Gastrointestinal, Dose 1	18	16
Any Headache, Dose 1	82	76
Grade 3 Headache, Dose 1	3	9
Related Headache, Dose 1	46	50
Any Joint Pain, Dose 1	34	38
Grade 3 Joint Pain, Dose 1	3	2
Related Joint Pain, Dose 1	25	29
Any Myalgia, Dose 1	70	84
Grade 3 Myalgia, Dose 1	3	5
Related Myalgia, Dose 1	55	72
Any Shivering, Dose 1	20	29
Grade 3 Shivering, Dose 1	0	3
Related Shivering, Dose 1	16	20
Any Fever, Dose 1	12	9
Fever (≥38.0°C), Dose 1	11	8
Grade 3 Fever, Dose 1	0	0
Related Fever, Dose 1	10	7
≥38.0°C Related Fever, Dose 1	9	6
Any Fatigue, Dose 2	8	4
Grade 3 Fatigue, Dose 2	0	0
Related Fatigue, Dose 2	4	4
Any Gastrointestinal, Dose 2	3	1
Grade 3 Gastrointestinal, Dose 2	0	0
Related Gastrointestinal, Dose 2	0	0
Any Headache, Dose 2	2	7
Grade 3 Headache, Dose 2	0	0
Related Headache, Dose 2	2	4
Any Joint Pain, Dose 2	2	4
Grade 3 Joint Pain, Dose 2	1	0
Related Joint Pain, Dose 2	1	3
Any Myalgia, Dose 2	3	9
Grade 3 Myalgia, Dose 2	1	0
Related Myalgia, Dose 2	2	7
Any Shivering, Dose 2	2	2
Grade 3 Shivering, Dose 2	0	0
Related Shivering, Dose 2	0	1
Any Fever, Dose 2	3	0
Fever (≥38.0°C), Dose 2	2	0
Grade 3 Fever, Dose 2	1	0
Related Fever, Dose 2	2	0
≥38.0°C Related Fever, Dose 2	1	0
Any Fatigue, Across Doses	97	101
Grade 3 Fatigue, Across Doses	8	13
Related Fatigue, Across Doses	66	72
Any Gastrointestinal, Across Doses	38	32
Grade 3 Gastrointestinal, Across Doses	2	1
Related Gastrointestinal, Across Doses	18	16
Any Headache, Across Doses	83	80
Grade 3 Headache, Across Doses	3	9
Related Headache, Across Doses	48	53
Any Joint Pain, Across Doses	35	42
Grade 3 Joint Pain, Across Doses	4	2
Related Joint Pain, Across Doses	25	32
Any Myalgia, Across Doses	71	88
Grade 3 Myalgia, Across Doses	4	5
Related Myalgia, Across Doses	56	76
Any Shivering, Across Doses	21	31
Grade 3 Shivering, Across Doses	0	3
Related Shivering, Across Doses	16	21
Any Fever, Across Doses	14	9
Fever (≥38.0°C), Across Doses	12	8
Grade 3 Fever, Across Doses	1	0
Related Fever, Across Doses	12	7
≥38.0°C Related Fever, Across Doses	10	6

No statistical analyses for this end point

Primary: Duration of solicited local AEs in subjects aged 3-17 years.

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End point title

Duration of solicited local AEs in subjects aged 3-17 years. ^[15] ^[16]

End point description

Duration was defined as number of days with any grade of local symptoms.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	243	253
Units: Days
median (full range (min-max))
Pain, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Pain, Dose 2	1.0 (1.0 to 5.0)	2.0 (1.0 to 3.0)
Redness, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Redness, Dose 2	2.0 (1.0 to 5.0)	1.0 (1.0 to 7.0)
Swelling, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Swelling, Dose 2	2.0 (1.0 to 5.0)	2.0 (1.0 to 7.0)

No statistical analyses for this end point

Primary: Duration of solicited general AEs in subjects aged 3-4 years.

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End point title

Duration of solicited general AEs in subjects aged 3-4 years. ^[17]

End point description

Duration was defined as number of days with any grade of general symptoms.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted

End point values	influsplit tetra_ip 3-4y group	influsplit tetra_lp 3-4y group
Number of subjects analysed	14	14
Units: Days
median (full range (min-max))
Drowsiness, Dose 1	1.0 (1.0 to 6.0)	1.0 (1.0 to 7.0)
Drowsiness, Dose 2	1.0 (1.0 to 2.0)	2.0 (1.0 to 5.0)
Irritability, Dose 1	2.0 (1.0 to 2.0)	1.0 (1.0 to 4.0)
Irritability, Dose 2	1.0 (1.0 to 1.0)	1.0 (1.0 to 7.0)
Loss of appetite, Dose 1	3.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Loss of appetite, Dose 2	1.0 (1.0 to 2.0)	4.0 (1.0 to 7.0)
Fever, Dose 1	2.0 (1.0 to 5.0)	1.0 (1.0 to 5.0)
Fever, Dose 2	99999 (99999 to 99999)	1.5 (1.0 to 3.0)

No statistical analyses for this end point

Primary: Duration of solicited general AEs in subjects aged 5-17 years.

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End point title

Duration of solicited general AEs in subjects aged 5-17 years. ^[18]

End point description

Duration was defined as number of days with any grade of general symptoms.

End point type

Primary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted

End point values	influsplit tetra_ip 5-17y group	influsplit tetra_lp 5-17y group
Number of subjects analysed	94	99
Units: Days
median (full range (min-max))
Fatigue, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 6.0)
Fatigue, Dose 2	1.0 (1.0 to 3.0)	1.5 (1.0 to 3.0)
Gastrointestinal symptoms, Dose 1	1.0 (1.0 to 6.0)	1.0 (1.0 to 5.0)
Gastrointestinal symptoms, Dose 2	2.0 (1.0 to 2.0)	1.0 (1.0 to 1.0)
Headache, Dose 1	1.0 (1.0 to 7.0)	2.0 (1.0 to 6.0)
Headache, Dose 2	2.5 (2.0 to 3.0)	2.0 (1.0 to 3.0)
Joint Pain, Dose 1	2.0 (1.0 to 7.0)	1.0 (1.0 to 5.0)
Joint Pain, Dose 2	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)
Myalgia, Dose 1	2.0 (1.0 to 5.0)	1.0 (1.0 to 5.0)
Myalgia, Dose 2	1.0 (1.0 to 2.0)	1.0 (1.0 to 3.0)
Shivering, Dose 1	1.0 (1.0 to 6.0)	1.0 (1.0 to 5.0)
Shivering, Dose 2	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)
Fever, Dose 1	1.0 (1.0 to 2.0)	1.0 (1.0 to 6.0)
Fever, Dose 2	2.0 (1.0 to 2.0)	99999 (99999 to 99999)

No statistical analyses for this end point

Primary: Number of subjects aged 3-17 years reporting solicited oculorespiratory syndrome (ORS) like symptoms.

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End point title

Number of subjects aged 3-17 years reporting solicited oculorespiratory syndrome (ORS) like symptoms. ^[19] ^[20]

End point description

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

End point type

Primary

End point timeframe

During the 3-day (Days 0-2) post-vaccination period

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	410	410
Units: Subjects
Any Chest Tightness, Dose 1	2	6
Grade 3 Chest Tightness, Dose 1	0	0
Related Chest Tightness, Dose 1	0	3
Any Cough, Dose 1	35	31
Grade 3 Cough, Dose 1	2	1
Related Cough, Dose 1	12	10
Any Difficulty Breathing, Dose 1	5	11
Grade 3 Difficulty Breathing, Dose 1	0	0
Related Difficulty Breathing, Dose 1	2	7
Any Hoarseness, Dose 1	10	12
Grade 3 Hoarseness, Dose 1	0	0
Related Hoarseness, Dose 1	2	6
Any Red Eyes, Dose 1	14	12
Grade 3 Red Eyes, Dose 1	0	0
Related Red Eyes, Dose 1	6	9
Any Sore throat, Dose 1	14	18
Grade 3 Sore throat, Dose 1	1	0
Related Sore throat, Dose 1	2	9
Any Swallowing Difficulty, Dose 1	5	6
Grade 3 Swallowing Difficulty, Dose 1	0	0
Related Swallowing Difficulty, Dose 1	1	3
Any Swelling of the face, Dose 1	3	2
Grade 3 Swelling of the face, Dose 1	0	0
Related Swelling of the face, Dose 1	3	2
Any Wheezing, Dose 1	1	5
Grade 3 Wheezing, Dose 1	0	0
Related Wheezing, Dose 1	1	4
Any Chest Tightness, Dose 2	0	0
Grade 3 Chest Tightness, Dose 2	0	0
Related Chest Tightness, Dose 2	0	0
Any Cough, Dose 2	6	13
Grade 3 Cough, Dose 2	0	2
Related Cough, Dose 2	1	1
Any Difficulty Breathing, Dose 2	0	2
Grade 3 Difficulty Breathing, Dose 2	0	0
Related Difficulty Breathing, Dose 2	0	0
Any Hoarseness, Dose 2	2	3
Grade 3 Hoarseness, Dose 2	0	0
Related Hoarseness, Dose 2	1	0
Any Red Eyes, Dose 2	0	1
Grade 3 Red Eyes, Dose 2	0	1
Related Red Eyes, Dose 2	0	1
Any Sore Throat, Dose 2	2	3
Grade 3 Sore Throat, Dose 2	0	1
Related Sore Throat, Dose 2	0	0
Any Swallowing Difficulty, Dose 2	2	1
Grade 3 Swallowing Difficulty, Dose 2	0	1
Related Swallowing Difficulty, Dose 2	1	0
Any Swelling of the face, Dose 2	0	1
Grade 3 Swelling of the face, Dose 2	0	0
Related Swelling of the face, Dose 2	0	0
Any Wheezing, Dose 2	0	2
Grade 3 Wheezing, Dose 2	0	0
Related Wheezing, Dose 2	0	0
Any Chest Tightness, Across Doses	2	6
Grade 3 Chest Tightness, Across Doses	0	0
Related Chest Tightness, Across Doses	0	3
Any Cough, Across Doses	39	39
Grade 3 Cough, Across Doses	2	3
Related Cough, Across Doses	13	11
Any Difficulty Breathing, Across Doses	5	13
Grade 3 Difficulty Breathing, Across Doses	0	0
Related Difficulty Breathing, Across Doses	2	7
Any Hoarseness, Across Doses	11	15
Grade 3 Hoarseness, Across Doses	0	0
Related Hoarseness, Across Doses	3	6
Any Red Eyes, Across Doses	14	13
Grade 3 Red Eyes, Across Doses	0	1
Related Red Eyes, Across Doses	6	10
Any Sore Throat, Across Doses	15	21
Grade 3 Sore Throat, Across Doses	1	1
Related Sore Throat, Across Doses	2	9
Any Swallowing Difficulty, Across Doses	6	7
Grade 3 Swallowing Difficulty, Across Doses	0	1
Related Swallowing Difficulty, Across Doses	2	3
Any Swelling of the face, Across Doses	3	3
Grade 3 Swelling of the face, Across Doses	0	0
Related Swelling of the face, Across Doses	3	2
Any Wheezing, Across Doses	1	7
Grade 3 Wheezing, Across Doses	0	0
Related Wheezing, Across Doses	1	4

No statistical analyses for this end point

Primary: Number of subjects aged 3-17 years reporting the occurrence of all Medically Attended Events (MAEs) .

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End point title

Number of subjects aged 3-17 years reporting the occurrence of all Medically Attended Events (MAEs) . ^[21] ^[22]

End point description

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was a MAE that prevented normal activities. Related was defined as a MAE assessed by the investigator to be causally related to the study vaccination.

End point type

Primary

End point timeframe

During the entire study period (approximately 28 days (primed subjects) and 56 days (unprimed subjects) following vaccination

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	410	411
Units: Subjects
Any MAE(s)	59	52
Grade 3 MAE(s)	7	6
Related MAE(s)	2	0

No statistical analyses for this end point

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related unsolicited adverse events (AEs)

Top of page

End point title

Number of subjects aged 18-49 years reporting any, grade 3 and related unsolicited adverse events (AEs) ^[23] ^[24]

End point description

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

End point type

Primary

End point timeframe

During the 21-day (Days 0-20) follow-up period after vaccination

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	60
Units: Subjects
Any Unsolicited AEs	14	14
Grade 3 Unsolicited AEs	3	2
Related Unsolicited AEs	2	1

No statistical analyses for this end point

Primary: Number of subjects aged 3-17 years reporting any, grade 3 and related unsolicited adverse events (AEs).

Top of page

End point title

Number of subjects aged 3-17 years reporting any, grade 3 and related unsolicited adverse events (AEs). ^[25] ^[26]

End point description

End point type

Primary

End point timeframe

During the 28-day (Days 0-27) follow-up period after vaccination

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	410	411
Units: Subjects
Any Unsolicited AEs	83	86
Grade 3 Unsolicited AEs	12	8
Related Unsolicited AEs	10	7

No statistical analyses for this end point

Primary: Number of subjects aged 6-35 months reporting fever ≥38ºC across doses.

Top of page

End point title

Number of subjects aged 6-35 months reporting fever ≥38ºC across doses. ^[27] ^[28]

End point description

End point type

Primary

End point timeframe

During 7 days (Days 0-6) post-vaccination

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	462	470
Units: Subjects
Any Fever	76	70
Fever (≥38°C)	72	69

No statistical analyses for this end point

Primary: Number of subjects aged 18-49 years, reporting any and related serious adverse events (SAEs)

Top of page

End point title

Number of subjects aged 18-49 years, reporting any and related serious adverse events (SAEs) ^[29] ^[30]

End point description

A serious adverse event was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.

End point type

Primary

End point timeframe

During the entire study period (approximately 21 days)

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	60	60
Units: Subjects
Any SAEs	1	1
Related SAEs	0	0

No statistical analyses for this end point

Primary: Number of subjects aged 3-17 years, reporting any and related serious adverse events (SAEs)

Top of page

End point title

Number of subjects aged 3-17 years, reporting any and related serious adverse events (SAEs) ^[31] ^[32]

End point description

End point type

Primary

End point timeframe

During the entire study period [approximately 28 days (primed subjects) and 56 days (unprimed subjects)]

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The scope of this primary endpoint was descriptive, no statistical analyses were conducted
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	410	411
Units: Subjects
Any SAEs	1	0
Related SAEs	0	0

No statistical analyses for this end point

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

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End point title

Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains. ^[33]

End point description

HI antibody titres were expressed as geometric mean titers (GMTs) and adjusted GMT ratios. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), FluA/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

End point type

Primary

End point timeframe

At Day 28 post last vaccination

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	403	402
Units: Titers
geometric mean (confidence interval 95%)
H1N1	698.0 (629.6 to 773.9)	694.1 (625.8 to 769.7)
H3N2	158.2 (143.7 to 174.2)	171.4 (156.3 to 188.0)
Yamagata	479.0 (434.1 to 528.5)	527.6 (475.5 to 585.3)
Victoria	237.6 (210.4 to 268.3)	253.7 (222.7 to 289.1)

Statistical analysis 1

Statistical analysis description

The adjusted GMT of HI antibodies for H1N1 strain at post-vaccination of each vaccine, the GMT ratio of Influsplit Tetra_LP/ Influsplit Tetra_IP and the 2-sided 95% CI on each GMT ratio were computed after fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination antibody titer as covariate.

Comparison groups

Influsplit Tetra_LP 3-17y Group v Influsplit Tetra_IP 3-17y Group

Number of subjects included in analysis

805

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[34]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.11

Notes
[34] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (D-QIV_LP/ D-QIV_IP) is ≤ 1.5.

Statistical analysis 2

Statistical analysis description

The adjusted GMT of HI antibodies for H3N2 strain at post-vaccination of each vaccine, the GMT ratio of Influsplit Tetra_LP/Influsplit Tetra_IP and the 2-sided 95% CI on each GMT ratio were computed after fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination antibody titer as covariate.

Comparison groups

Influsplit Tetra_LP 3-17y Group v Influsplit Tetra_IP 3-17y Group

Number of subjects included in analysis

805

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.18

Notes
[35] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/ Influsplit Tetra_IP) is ≤ 1.5.

Statistical analysis 3

Statistical analysis description

The adjusted GMT of HI antibodies for Yamagata strain at post-vaccination of each vaccine, the GMT ratio of Influsplit Tetra_LP/Influsplit Tetra_IP and the 2-sided 95% CI on each GMT ratio were computed after fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination antibody titer as covariate.

Comparison groups

Influsplit Tetra_LP 3-17y Group v Influsplit Tetra_IP 3-17y Group

Number of subjects included in analysis

805

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[36]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.16

Notes
[36] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/ Influsplit Tetra_IP) is ≤ 1.5

Statistical analysis 4

Statistical analysis description

The adjusted GMT of HI antibodies for Victoria strain at post-vaccination of each vaccine, the GMT ratio of Influsplit Tetra_LP/Influsplit Tetra_IP and the 2-sided 95% CI on each GMT ratio were computed after fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination antibody titer as covariate.

Comparison groups

Influsplit Tetra_LP 3-17y Group v Influsplit Tetra_IP 3-17y Group

Number of subjects included in analysis

805

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.21

Notes
[37] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/ Influsplit Tetra_IP) is ≤ 1.5.

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

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End point title

Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains. ^[38]

End point description

End point type

Primary

End point timeframe

At Day 28 post last vaccination

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	432	427
Units: Titers
geometric mean (confidence interval 95%)
H1N1	97.5 (82.1 to 115.7)	105.5 (88.2 to 126.1)
H3N2	45.2 (39.0 to 52.3)	59.9 (51.7 to 69.4)
Yamagata	100.8 (87.8 to 115.8)	105.4 (91.8 to 121.0)
Victoria	32.1 (28.1 to 36.7)	38.0 (33.2 to 43.5)

Statistical analysis 1

Statistical analysis description

The adjusted GMT of HI antibodies for H1N1 strain at post-vaccination of each vaccine, the GMT ratio of Influsplit Tetra_LP/Influsplit Tetra_IP and the 2-sided 95% CI on each GMT ratio were computed after fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination antibody titer as covariate.

Comparison groups

Influsplit Tetra_LP 6-35m Group v Influsplit Tetra_IP 6-35m Group

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[39]

Method

ANCOVA

Parameter type

Adjusted GMT ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.28

Notes
[39] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/Influsplit Tetra_IP) is ≤ 1.5.

Statistical analysis 2

Statistical analysis description

Comparison groups

Influsplit Tetra_LP 6-35m Group v Influsplit Tetra_IP 6-35m Group

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[40]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.39

Notes
[40] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/Influsplit Tetra_IP) is ≤ 1.5

Statistical analysis 3

Statistical analysis description

Comparison groups

Influsplit Tetra_LP 6-35m Group v Influsplit Tetra_IP 6-35m Group

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[41]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.27

Notes
[41] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/Influsplit Tetra_IP) is ≤ 1.5.

Statistical analysis 4

Statistical analysis description

Comparison groups

Influsplit Tetra_LP 6-35m Group v Influsplit Tetra_IP 6-35m Group

Number of subjects included in analysis

859

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[42]

Method

ANCOVA

Parameter type

Adjusted GMT Ratio

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.38

Notes
[42] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Influsplit Tetra_LP/Influsplit Tetra_IP) is ≤ 1.5.

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 18-49 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Top of page

End point title

Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 18-49 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains ^[43]

End point description

HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

End point type

Secondary

End point timeframe

At Day 0 and Day 21

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	57	58
Units: Titers
geometric mean (confidence interval 95%)
[H1N1, Day 0]	48.3 (33.4 to 69.7)	53.6 (36.8 to 78.0)
[H1N1, Day 21]	655.7 (493.1 to 871.9)	632.2 (498.8 to 801.3)
[H3N2, Day 0]	16.7 (12.6 to 22.2)	16.0 (11.9 to 21.5)
[H3N2, Day 21	80.5 (63.2 to 102.7)	73.0 (59.0 to 90.5)
[Yamagata, Day 0]	133.3 (98.4 to 180.6)	101.6 (76.2 to 135.4)
[Yamagata, Day 21]	591.4 (475.1 to 736.3)	598.6 (480.9 to 745.0)
[Victoria, Day 0]	38.6 (29.5 to 50.5)	34.8 (25.2 to 48.1)
[Victoria, Day 21]	263.4 (209.0 to 331.9)	302.9 (244.0 to 376.1)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects aged 18-49 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of seroconverted subjects aged 18-49 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[44]

End point description

A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

End point type

Secondary

End point timeframe

At Day 21

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	57	57
Units: Subjects
H1N1	42	42
H3N2	30	29
Yamagata	27	36
Victoria	36	40

No statistical analyses for this end point

Secondary: Number of subjects aged 18-49 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of subjects aged 18-49 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[45]

End point description

A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

End point type

Secondary

End point timeframe

At Day 0 and Day 21

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	57	58
Units: Subjects
[H1N1, Day 0]	35	35
[H1N1, Day 21]	56	57
[H3N2, Day 0]	15	14
[H3N2, Day 21]	49	49
[Yamagata, Day 0]	52	50
[Yamagata, Day 21]	57	57
[Victoria, Day 0]	34	32
[Victoria, Day 21]	57	57

No statistical analyses for this end point

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 18-49 years.

Top of page

End point title

Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 18-49 years. ^[46]

End point description

MGI was defined as the fold increase in serum haemagglutination inhibition (HI) GMTs post-vaccination compared to pre-vaccination (Day 0). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

End point type

Secondary

End point timeframe

At Day 21

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group
Number of subjects analysed	57	57
Units: Fold increase
geometric mean (confidence interval 95%)
H1N1	13.6 (8.9 to 20.8)	11.5 (7.7 to 17.0)
H3N2	4.8 (3.6 to 6.5)	4.6 (3.6 to 5.7)
Yamagata	4.4 (3.3 to 6.0)	6.0 (4.3 to 8.2)
Victoria	6.8 (5.0 to 9.2)	8.6 (6.0 to 12.3)

No statistical analyses for this end point

Secondary: Number of subjects aged 5-17 years reporting myalgia across doses.

Top of page

End point title

Number of subjects aged 5-17 years reporting myalgia across doses.

End point description

Any = occurrence of any myalgia symptom regardless of intensity grade or relationship to vaccination.

End point type

Secondary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

End point values	influsplit tetra_ip 5-17y group	influsplit tetra_lp 5-17y group
Number of subjects analysed	340	338
Units: Subjects
Subjects	71	88

No statistical analyses for this end point

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Top of page

End point title

Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains ^[47]

End point description

End point type

Secondary

End point timeframe

At Day 0 and Day 28 post last vaccination

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	403	402
Units: Titers
geometric mean (confidence interval 95%)
[H1N1, Day 0]	80.2 (69.2 to 93.0)	87.7 (76.1 to 101.0)
[H1N1, Day 28]	698.0 (629.6 to 773.9)	694.1 (625.8 to 769.7)
[H3N2, Day 0]	38.9 (34.6 to 43.8)	41.9 (37.1 to 47.3)
[H3N2, Day 28]	158.2 (143.7 to 174.2)	171.4 (156.3 to 188.0)
[Yamagata, Day 0]	58.1 (49.7 to 68.0)	70.8 (60.4 to 83.0)
[Yamagata, Day 28]	479.0 (434.1 to 528.5)	527.6 (475.5 to 585.3)
[Victoria, Day 0]	27.3 (23.8 to 31.3)	28.8 (25.0 to 33.1)
[Victoria, Day 28]	237.6 (210.4 to 268.3)	253.7 (222.7 to 289.1)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects aged 3-17 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of seroconverted subjects aged 3-17 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[48]

End point description

End point type

Secondary

End point timeframe

At Day 28 post last vaccination

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	403	402
Units: Subjects
H1N1	274	269
H3N2	192	183
Yamagata	273	268
Victoria	285	287

No statistical analyses for this end point

Secondary: Number of subjects aged 3-17 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of subjects aged 3-17 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[49]

End point description

End point type

Secondary

End point timeframe

At Day 0 and Day 28 post last vaccination

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	403	402
Units: Subjects
[H1N1, Day 0]	308	314
[H1N1, Day 28]	393	395
[H3N2, Day 0]	245	252
[H3N2, Day 28]	377	378
[Yamagata, Day 0]	266	281
[Yamagata, Day 28]	396	395
[Victoria, Day 0]	192	195
[Victoria, Day 28]	375	374

No statistical analyses for this end point

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 3-17 years.

Top of page

End point title

Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 3-17 years. ^[50]

End point description

End point type

Secondary

End point timeframe

At Day 28 post last vaccination

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 3-17y Group	Influsplit Tetra_LP 3-17y Group
Number of subjects analysed	403	402
Units: Fold increase
geometric mean (confidence interval 95%)
H1N1	8.7 (7.6 to 10.0)	7.9 (6.9 to 9.1)
H3N2	4.1 (3.7 to 4.5)	4.1 (3.7 to 4.6)
Yamagata	8.2 (7.2 to 9.4)	7.4 (6.5 to 8.5)
Victoria	8.7 (7.7 to 9.8)	8.8 (7.7 to 10.0)

No statistical analyses for this end point

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Top of page

End point title

Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains ^[51]

End point description

End point type

Secondary

End point timeframe

At Day 0 and Day 28 post last vaccination

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	432	427
Units: Titers
geometric mean (confidence interval 95%)
H1N1, Day 0	11.1 (9.6 to 12.8)	11.2 (9.7 to 12.9)
H1N1, Day 28	97.5 (82.1 to 115.7)	105.5 (88.2 to 126.1)
H3N2, Day 0	7.5 (6.8 to 8.2)	8.4 (7.5 to 9.3)
H3N2, Day 28	45.2 (39.0 to 52.3)	59.9 (51.7 to 69.4)
Yamagata, Day 0	8.3 (7.5 to 9.1)	7.9 (7.2 to 8.6)
Yamagata, Day 28	100.8 (87.8 to 115.8)	105.4 (91.8 to 121.0)
Victoria, Day 0	5.7 (5.4 to 6.1)	5.7 (5.4 to 6.1)
Victoria, Day 28	32.1 (28.1 to 36.7)	38.0 (33.2 to 43.5)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects aged 6-35 months for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of seroconverted subjects aged 6-35 months for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[52]

End point description

End point type

Secondary

End point timeframe

At Day 28 post last vaccination

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	432	427
Units: Subjects
H1N1	287	275
H3N2	217	236
Yamagata	318	321
Victoria	213	211

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Top of page

End point title

Number of subjects aged 6-35 months, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains. ^[53]

End point description

End point type

Secondary

End point timeframe

At Day 0 and Day 28 post last vaccination

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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	432	427
Units: Subjects
H1N1, Day 0	84	83
H1N1, Day 28	303	289
H3N2, Day 0	55	67
H3N2, Day 28	232	259
Yamagata, Day 0	53	49
Yamagata, Day 28	329	331
Victoria, Day 0	17	16
Victoria, Day 28	214	217

No statistical analyses for this end point

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 6-35 months.

Top of page

End point title

Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 6-35 months. ^[54]

End point description

End point type

Secondary

End point timeframe

At Day 28 post last vaccination

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	432	427
Units: Fold increase
geometric mean (confidence interval 95%)
H1N1	8.8 (7.8 to 10.0)	9.5 (8.3 to 10.8)
H3N2	6.0 (5.4 to 6.8)	7.1 (6.3 to 7.9)
Yamagata	12.2 (10.8 to 13.8)	13.3 (11.8 to 15.0)
Victoria	5.6 (5.0 to 6.3)	6.6 (5.8 to 7.4)

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting fever ≥38ºC after Dose 1 and after Dose 2.

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End point title

Number of subjects aged 6-35 months reporting fever ≥38ºC after Dose 1 and after Dose 2. ^[55]

End point description

Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Fever = temperature of ≥ 38°C/100.4°F by any route

End point type

Secondary

End point timeframe

During 7 days (Days 0-6) post-vaccination

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	462	470
Units: Subjects
Any Fever, Dose 1	42	44
Fever (≥38°C), Dose 1	39	42
Any Fever, Dose 2	41	40
Fever (≥38°C), Dose 2	40	40

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting solicited local adverse events (AEs).

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End point title

Number of subjects aged 6-35 months reporting solicited local adverse events (AEs). ^[56]

End point description

End point type

Secondary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[56] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	462	470
Units: Subjects
Any Pain, Dose 1	69	77
Grade 3 Pain, Dose 1	1	2
Any Redness, Dose 1	88	86
Grade 3 Redness, Dose 1	0	0
Any Swelling, Dose 1	33	42
Grade 3 Swelling, Dose 1	0	0
Any Pain, Dose 2	47	48
Grade 3 Pain, Dose 2	1	4
Any Redness, Dose 2	61	66
Grade 3 Redness, Dose 2	0	0
Any Swelling, Dose 2	32	27
Grade 3 Swelling, Dose 2	0	1
Any Pain, Across Doses	89	98
Grade 3 Pain, Across Doses	2	4
Any Redness, Across Doses	106	106
Grade 3 Redness, Across Doses	0	0
Any Swelling, Across Doses	50	51
Grade 3 Swelling, Across Doses	0	1

No statistical analyses for this end point

Secondary: Number of subjects aged 6 months to <5 years, reporting fever ≥38ºC (100.4°F) and >39.0°C (102.2ºF) across doses.

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End point title

Number of subjects aged 6 months to <5 years, reporting fever ≥38ºC (100.4°F) and >39.0°C (102.2ºF) across doses.

End point description

Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever = temperature above 39.0°C/102.2ºF. Data of 2 independent groups were pooled.

End point type

Secondary

End point timeframe

During the 2 days (Day 0-Day 1) post-vaccination period

End point values	influsplit tetra_ip 6m-<5y group	influsplit tetra_lp 6m-<5y group
Number of subjects analysed	532	542
Units: Subjects
Any Fever	29	31
Fever (≥38°C)	28	31
Grade 3 Fever	4	1

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting any, grade 3 and related solicited general symptoms.

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End point title

Number of subjects aged 6-35 months reporting any, grade 3 and related solicited general symptoms. ^[57]

End point description

End point type

Secondary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[57] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	462	470
Units: Subjects
Any Drowsiness, Dose 1	87	77
Grade 3 Drowsiness, Dose 1	3	7
Related Drowsiness, Dose 1	54	50
Any Irritability, Dose 1	124	96
Grade 3 Irritability, Dose 1	10	10
Related Irritability, Dose 1	75	58
Any Loss of appetite, Dose 1	94	76
Grade 3 Loss of appetite, Dose 1	9	8
Related Loss of appetite, Dose 1	47	40
Any Fever, Dose 1	42	44
Fever (≥38.0°C), Dose 1	39	42
Grade 3 Fever, Dose 1	8	5
Related Fever, Dose 1	16	23
≥38.0°C Related Fever, Dose 1	14	22
Any Drowsiness, Dose 2	63	58
Grade 3 Drowsiness, Dose 2	6	7
Related Drowsiness, Dose 2	46	35
Any Irritability, Dose 2	87	87
Grade 3 Irritability, Dose 2	5	8
Related Irritability, Dose 2	59	50
Any Loss Of Appetite, Dose 2	64	69
Grade 3 Loss Of Appetite, Dose 2	4	10
Related Loss Of Appetite, Dose 2	39	37
Any Fever, Dose 2	41	40
Fever (≥38.0°C), Dose 2	40	40
Grade 3 Fever, Dose 2	10	9
Related Fever, Dose 2	19	17
≥38.0°C Related Fever, Dose 2	19	17
Any Drowsiness, Across Doses	115	103
Grade 3 Drowsiness, Across Doses	8	13
Related Drowsiness, Across Doses	78	66
Any Irritability, Across Doses	155	141
Grade 3 Irritability, Across Doses	15	17
Related Irritability, Across Doses	98	87
Any Loss Of Appetite, Across Doses	127	116
Grade 3 Loss Of Appetite, Across Doses	13	17
Related Loss Of Appetite, Across Doses	69	61
Any Fever, Across Doses	76	70
Fever (≥38.0°C), Across Doses	72	69
Grade 3 Fever, Across Doses	18	14
Related Fever, Across Doses	32	35
≥38.0°C Related Fever, Across Doses	30	34

No statistical analyses for this end point

Secondary: Duration of solicited local AEs in subjects aged 6-35 months.

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End point title

Duration of solicited local AEs in subjects aged 6-35 months. ^[58]

End point description

Duration was defined as number of days with any grade of local symptoms.

End point type

Secondary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[58] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	88	86
Units: Days
median (full range (min-max))
Pain, Dose 1	1.0 (1.0 to 6.0)	1.0 (1.0 to 7.0)
Pain, Dose 2	2.0 (1.0 to 5.0)	2.0 (1.0 to 6.0)
Redness, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Redness, Dose 2	2.0 (1.0 to 7.0)	2.0 (1.0 to 6.0)
Swelling, Dose 1	1.0 (1.0 to 7.0)	1.0 (1.0 to 7.0)
Swelling, Dose 2	2.0 (1.0 to 7.0)	2.0 (1.0 to 5.0)

No statistical analyses for this end point

Secondary: Duration of solicited general AEs in subjects aged 6-35 months.

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End point title

Duration of solicited general AEs in subjects aged 6-35 months. ^[59]

End point description

Duration was defined as number of days with any grade of general symptoms.

End point type

Secondary

End point timeframe

During the 7-day (Days 0-6) post-vaccination period

Notes
[59] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	124	96
Units: Days
median (full range (min-max))
Drowsiness, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Drowsiness, Dose 2	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Irritability, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Irritability, Dose 2	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Loss of appetite, Dose 1	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Loss of appetite, Dose 2	2.0 (1.0 to 7.0)	2.0 (1.0 to 7.0)
Fever, Dose 1	2.0 (1.0 to 5.0)	1.0 (1.0 to 4.0)
Fever, Dose 2	1.0 (1.0 to 5.0)	2.0 (1.0 to 5.0)

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting solicited oculorespiratory syndrome (ORS) like symptoms.

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End point title

Number of subjects aged 6-35 months reporting solicited oculorespiratory syndrome (ORS) like symptoms. ^[60]

End point description

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

End point type

Secondary

End point timeframe

During a 3 day (Days 0-2) follow-up period after vaccination

Notes
[60] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	462	470
Units: Subjects
Any Chest Tightness, Dose 1	2	1
Grade 3 Chest Tightness, Dose 1	0	0
Related Chest Tightness, Dose 1	0	0
Any Cough, Dose 1	47	50
Grade 3 Cough, Dose 1	3	3
Related Cough, Dose 1	16	13
Any Difficulty Breathing, Dose 1	15	12
Grade 3 Difficulty Breathing, Dose 1	1	1
Related Difficulty Breathing, Dose 1	4	2
Any Hoarseness, Dose 1	13	11
Grade 3 Hoarseness, Dose 1	0	0
Related Hoarseness, Dose 1	1	4
Any Red Eyes, Dose 1	10	11
Grade 3 Red Eyes, Dose 1	0	0
Related Red Eyes, Dose 1	6	5
Any Sore throat, Dose 1	6	7
Grade 3 Sore throat, Dose 1	0	0
Related Sore throat, Dose 1	1	3
Any Swallowing Difficulty, Dose 1	1	5
Grade 3 Swallowing Difficulty, Dose 1	0	0
Related Swallowing Difficulty, Dose 1	0	2
Any Swelling of the face, Dose 1	4	3
Grade 3 Swelling of the face, Dose 1	0	0
Related Swelling of the face, Dose 1	1	1
Any Wheezing, Dose 1	9	12
Grade 3 Wheezing, Dose 1	1	1
Related Wheezing, Dose 1	3	3
Any Chest Tightness, Dose 2	9	4
Grade 3 Chest Tightness, Dose 2	0	2
Related Chest Tightness, Dose 2	0	1
Any Cough, Dose 2	37	53
Grade 3 Cough, Dose 2	5	3
Related Cough, Dose 2	8	8
Any Difficulty Breathing, Dose 2	19	18
Grade 3 Difficulty Breathing, Dose 2	1	2
Related Difficulty Breathing, Dose 2	5	3
Any Hoarseness, Dose 2	13	9
Grade 3 Hoarseness, Dose 2	0	1
Related Hoarseness, Dose 2	1	1
Any Red Eyes, Dose 2	10	11
Grade 3 Red Eyes, Dose 2	0	0
Related Red Eyes, Dose 2	6	1
Any Sore Throat, Dose 2	7	11
Grade 3 Sore Throat, Dose 2	1	1
Related Sore Throat, Dose 2	0	2
Any Swallowing Difficulty, Dose 2	8	7
Grade 3 Swallowing Difficulty, Dose 2	2	1
Related Swallowing Difficulty, Dose 2	0	1
Any Swelling of the face, Dose 2	5	4
Grade 3 Swelling of the face, Dose 2	0	0
Related Swelling of the face, Dose 2	1	1
Any Wheezing, Dose 2	11	16
Grade 3 Wheezing, Dose 2	3	1
Related Wheezing, Dose 2	4	3
Any Chest Tightness, Across Doses	10	5
Grade 3 Chest Tightness, Across Doses	0	2
Related Chest Tightness, Across Doses	0	1
Any Cough, Across Doses	73	85
Grade 3 Cough, Across Doses	8	6
Related Cough, Across Doses	22	18
Any Difficulty Breathing, Across Doses	31	25
Grade 3 Difficulty Breathing, Across Doses	2	3
Related Difficulty Breathing, Across Doses	8	4
Any Hoarseness, Across Doses	23	17
Grade 3 Hoarseness, Across Doses	0	1
Related Hoarseness, Across Doses	2	5
Any Red Eyes, Across Doses	18	19
Grade 3 Red Eyes, Across Doses	0	0
Related Red Eyes, Across Doses	10	5
Any Sore Throat, Across Doses	12	17
Grade 3 Sore Throat, Across Doses	1	1
Related Sore Throat, Across Doses	1	5
Any Swallowing Difficulty, Across Doses	8	12
Grade 3 Swallowing Difficulty, Across Doses	2	1
Related Swallowing Difficulty, Across Doses	0	3
Any Swelling of the face, Across Doses	9	7
Grade 3 Swelling of the face,Across Doses	0	0
Related Swelling of the face,Across Doses	2	2
Any Wheezing, Across Doses	19	26
Grade 3 Wheezing, Across Doses	4	2
Related Wheezing, Across Doses	7	5

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting the occurrence of all Medically Attended Events (MAEs)

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End point title

Number of subjects aged 6-35 months reporting the occurrence of all Medically Attended Events (MAEs) ^[61]

End point description

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was a MAE that prevented normal activities. Related was defined as a MAE assessed by the investigator to be causally related to the study vaccination.

End point type

Secondary

End point timeframe

During the entire study period (approximately 28 days (primed subjects) and 56 days (unprimed subjects) following vaccination

Notes
[61] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	466	474
Units: Subjects
Any MAE(s)	235	252
Grade 3 MAE(s)	35	29
Related MAE(s)	2	0

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months reporting any, grade 3 and related unsolicited adverse events (AEs).

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End point title

Number of subjects aged 6-35 months reporting any, grade 3 and related unsolicited adverse events (AEs). ^[62]

End point description

End point type

Secondary

End point timeframe

During the 28-day (Days 0-27) follow-up period after vaccination

Notes
[62] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	466	474
Units: Subjects
Any Unsolicited AEs	243	262
Grade 3 Unsolicited AEs	33	31
Related Unsolicited AEs	6	3

No statistical analyses for this end point

Secondary: Number of subjects aged 6-35 months, reporting any and related serious adverse events (SAEs)

Top of page

End point title

Number of subjects aged 6-35 months, reporting any and related serious adverse events (SAEs) ^[63]

End point description

End point type

Secondary

End point timeframe

During the entire study period [approximately 28 days (primed subjects) and 56 days (unprimed subjects)]

Notes
[63] - 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: Descriptive analyses were performed based on the vaccine groups / vaccine administered in the study

End point values	Influsplit Tetra_IP 6-35m Group	Influsplit Tetra_LP 6-35m Group
Number of subjects analysed	466	474
Units: Subjects
Any SAEs	7	11
Related SAEs	0	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Serious Adverse Events: From Day 0 to Day 56; Solicited local and genera l symptoms: During the 7-day (Days 0-6) post-vaccination period; Unsolicited adverse events: During the 28-day (Days 0-27) post-vaccination period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Influsplit Tetra_IP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_LP Adult Group

Reporting group description

Reporting group title

Influsplit Tetra_IP 3-17 y

Reporting group description

Reporting group title

Influsplit Tetra_LP 3-17 y

Reporting group description

Reporting group title

Influsplit Tetra_IP 6-35 m

Reporting group description

Reporting group title

Influsplit Tetra_LP 6-35 m

Reporting group description

Serious adverse events	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group	Influsplit Tetra_IP 3-17 y	Influsplit Tetra_LP 3-17 y	Influsplit Tetra_IP 6-35 m	Influsplit Tetra_LP 6-35 m
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 60 (1.67%)	1 / 60 (1.67%)	1 / 410 (0.24%)	0 / 411 (0.00%)	7 / 466 (1.50%)	11 / 474 (2.32%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Post procedural inflammation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchospasm
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Meningitis viral
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 410 (0.24%)	0 / 411 (0.00%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	3 / 466 (0.64%)	2 / 474 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	2 / 466 (0.43%)	2 / 474 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	2 / 474 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenovirus infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epstein-Barr virus infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemophilus infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudocroup
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 410 (0.00%)	0 / 411 (0.00%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Influsplit Tetra_IP Adult Group	Influsplit Tetra_LP Adult Group	Influsplit Tetra_IP 3-17 y	Influsplit Tetra_LP 3-17 y	Influsplit Tetra_IP 6-35 m	Influsplit Tetra_LP 6-35 m
Total subjects affected by non serious adverse events
subjects affected / exposed	51 / 60 (85.00%)	42 / 60 (70.00%)	327 / 410 (79.76%)	324 / 411 (78.83%)	315 / 466 (67.60%)	319 / 474 (67.30%)
Nervous system disorders
Headache
subjects affected / exposed	31 / 60 (51.67%)	16 / 60 (26.67%)	85 / 410 (20.73%)	84 / 411 (20.44%)	0 / 466 (0.00%)	1 / 474 (0.21%)
occurrences all number	32	17	89	88	0	1
Somnolence
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	16 / 410 (3.90%)	11 / 411 (2.68%)	115 / 466 (24.68%)	103 / 474 (21.73%)
occurrences all number	0	0	19	13	150	135
General disorders and administration site conditions
Chills
subjects affected / exposed	9 / 60 (15.00%)	7 / 60 (11.67%)	21 / 410 (5.12%)	31 / 411 (7.54%)	1 / 466 (0.21%)	0 / 474 (0.00%)
occurrences all number	9	7	22	31	1	0
Fatigue
subjects affected / exposed	32 / 60 (53.33%)	20 / 60 (33.33%)	97 / 410 (23.66%)	101 / 411 (24.57%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences all number	32	20	102	103	0	0
Pain
subjects affected / exposed	41 / 60 (68.33%)	32 / 60 (53.33%)	252 / 410 (61.46%)	264 / 411 (64.23%)	89 / 466 (19.10%)	98 / 474 (20.68%)
occurrences all number	41	32	279	294	117	125
Pyrexia
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	21 / 410 (5.12%)	24 / 411 (5.84%)	95 / 466 (20.39%)	92 / 474 (19.41%)
occurrences all number	0	0	22	25	112	111
Swelling
subjects affected / exposed	2 / 60 (3.33%)	4 / 60 (6.67%)	109 / 410 (26.59%)	110 / 411 (26.76%)	50 / 466 (10.73%)	51 / 474 (10.76%)
occurrences all number	2	4	118	117	65	69
Gastrointestinal disorders
Gastrointestinal disorder
subjects affected / exposed	6 / 60 (10.00%)	6 / 60 (10.00%)	38 / 410 (9.27%)	32 / 411 (7.79%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences all number	6	6	38	33	0	0
Dysphagia
subjects affected / exposed	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 410 (0.00%)	0 / 411 (0.00%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences all number	3	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 60 (5.00%)	2 / 60 (3.33%)	43 / 410 (10.49%)	44 / 411 (10.71%)	86 / 466 (18.45%)	100 / 474 (21.10%)
occurrences all number	3	2	46	51	99	124
Dyspnoea
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	6 / 410 (1.46%)	13 / 411 (3.16%)	31 / 466 (6.65%)	25 / 474 (5.27%)
occurrences all number	0	0	6	13	34	30
Oropharyngeal pain
subjects affected / exposed	4 / 60 (6.67%)	3 / 60 (5.00%)	16 / 410 (3.90%)	23 / 411 (5.60%)	13 / 466 (2.79%)	18 / 474 (3.80%)
occurrences all number	4	3	17	23	14	20
Wheezing
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 410 (0.24%)	7 / 411 (1.70%)	19 / 466 (4.08%)	26 / 474 (5.49%)
occurrences all number	0	0	1	7	20	28
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	131 / 410 (31.95%)	128 / 411 (31.14%)	106 / 466 (22.75%)	107 / 474 (22.57%)
occurrences all number	0	0	145	140	149	153
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	10 / 410 (2.44%)	16 / 411 (3.89%)	155 / 466 (33.26%)	141 / 474 (29.75%)
occurrences all number	0	0	11	20	211	183
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 60 (13.33%)	5 / 60 (8.33%)	35 / 410 (8.54%)	42 / 411 (10.22%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences all number	8	5	36	43	0	0
Myalgia
subjects affected / exposed	21 / 60 (35.00%)	13 / 60 (21.67%)	72 / 410 (17.56%)	90 / 411 (21.90%)	0 / 466 (0.00%)	0 / 474 (0.00%)
occurrences all number	21	13	74	96	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	5 / 410 (1.22%)	4 / 411 (0.97%)	39 / 466 (8.37%)	56 / 474 (11.81%)
occurrences all number	0	0	5	4	49	64
Gastroenteritis
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	2 / 410 (0.49%)	4 / 411 (0.97%)	31 / 466 (6.65%)	37 / 474 (7.81%)
occurrences all number	0	0	2	4	33	44
Nasopharyngitis
subjects affected / exposed	1 / 60 (1.67%)	4 / 60 (6.67%)	4 / 410 (0.98%)	6 / 411 (1.46%)	26 / 466 (5.58%)	29 / 474 (6.12%)
occurrences all number	1	4	4	6	27	30
Upper respiratory tract infection
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	13 / 410 (3.17%)	17 / 411 (4.14%)	62 / 466 (13.30%)	73 / 474 (15.40%)
occurrences all number	0	0	14	18	80	82
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 60 (0.00%)	0 / 60 (0.00%)	13 / 410 (3.17%)	16 / 411 (3.89%)	127 / 466 (27.25%)	116 / 474 (24.47%)
occurrences all number	0	0	13	20	158	145

More information

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Were there any global substantial amendments to the protocol? Yes

13 Aug 2013

Amendment 1: As a result of the recent meeting (25 June 2014) of the United States Advisory Committee on Immunization Practices (ACIP), a slightly modified influenza vaccination dosing schedule will be recommended for the 2014-15 influenza season for children 6 months to < 9 years of age since the vaccine strains did not change from last year’s (2013-14) influenza season. Consequently, the dosing schedule described in the initial protocol (dated 07 April 2014) could result in one extra dose for some study participants compared to the ACIP recommendation for the 2014-15 influenza season. Therefore, the definitions of vaccine primed and unprimed subjects have been changed in the current protocol amendment (see ‘Glossary of Terms’ section) to harmonize with the ACIP recommendations for the 2014-15 influenza season, in order to follow the updated recommended ACIP dosing schedule.

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: Number of subjects aged 18-49 years reporting solicited local adverse events (AEs).

Primary: Number of subjects aged 18-49 years reporting solicited local adverse events (AEs).

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related solicited general symptoms.

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related solicited general symptoms.

Primary: Duration of solicited local and general AEs in subjects aged 18-49 years.

Primary: Duration of solicited local and general AEs in subjects aged 18-49 years.

Primary: Number of subjects aged 18-49 years reporting solicited Oculorespiratory Syndrome (ORS) like symptoms.

Primary: Number of subjects aged 18-49 years reporting solicited Oculorespiratory Syndrome (ORS) like symptoms.

Primary: Number of subjects aged 18-49 years reporting the occurrence of medically attended events (MAEs).

Primary: Number of subjects aged 18-49 years reporting the occurrence of medically attended events (MAEs).

Primary: Number of subjects aged 3-17 years reporting solicited local adverse events (AEs).

Primary: Number of subjects aged 3-17 years reporting solicited local adverse events (AEs).

Primary: Number of subjects aged 3-4 years reporting any, grade 3 and related solicited general symptoms.

Primary: Number of subjects aged 3-4 years reporting any, grade 3 and related solicited general symptoms.

Primary: Number of subjects aged 5-17 years reporting any, grade 3 and related solicited general symptoms.

Primary: Number of subjects aged 5-17 years reporting any, grade 3 and related solicited general symptoms.

Primary: Duration of solicited local AEs in subjects aged 3-17 years.

Primary: Duration of solicited local AEs in subjects aged 3-17 years.

Primary: Duration of solicited general AEs in subjects aged 3-4 years.

Primary: Duration of solicited general AEs in subjects aged 3-4 years.

Primary: Duration of solicited general AEs in subjects aged 5-17 years.

Primary: Duration of solicited general AEs in subjects aged 5-17 years.

Primary: Number of subjects aged 3-17 years reporting solicited oculorespiratory syndrome (ORS) like symptoms.

Primary: Number of subjects aged 3-17 years reporting solicited oculorespiratory syndrome (ORS) like symptoms.

Primary: Number of subjects aged 3-17 years reporting the occurrence of all Medically Attended Events (MAEs) .

Primary: Number of subjects aged 3-17 years reporting the occurrence of all Medically Attended Events (MAEs) .

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related unsolicited adverse events (AEs)

Primary: Number of subjects aged 18-49 years reporting any, grade 3 and related unsolicited adverse events (AEs)

Primary: Number of subjects aged 3-17 years reporting any, grade 3 and related unsolicited adverse events (AEs).

Primary: Number of subjects aged 3-17 years reporting any, grade 3 and related unsolicited adverse events (AEs).

Primary: Number of subjects aged 6-35 months reporting fever ≥38ºC across doses.

Primary: Number of subjects aged 6-35 months reporting fever ≥38ºC across doses.

Primary: Number of subjects aged 18-49 years, reporting any and related serious adverse events (SAEs)

Primary: Number of subjects aged 18-49 years, reporting any and related serious adverse events (SAEs)

Primary: Number of subjects aged 3-17 years, reporting any and related serious adverse events (SAEs)

Primary: Number of subjects aged 3-17 years, reporting any and related serious adverse events (SAEs)

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

Primary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum antihaemagglutination (HA) antibody titers against the 4 vaccine strains.

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 18-49 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 18-49 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Number of seroconverted subjects aged 18-49 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of seroconverted subjects aged 18-49 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 18-49 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 18-49 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 18-49 years.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 18-49 years.

Secondary: Number of subjects aged 5-17 years reporting myalgia across doses.

Secondary: Number of subjects aged 5-17 years reporting myalgia across doses.

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 3-17 years by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Number of seroconverted subjects aged 3-17 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of seroconverted subjects aged 3-17 years for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 3-17 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 3-17 years, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 3-17 years.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 3-17 years.

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects aged 6-35 months by calculating serum anti-haemagglutination (HA) antibody titers against the 4 vaccine strains

Secondary: Number of seroconverted subjects aged 6-35 months for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of seroconverted subjects aged 6-35 months for anti- Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 6-35 months, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Number of subjects aged 6-35 months, who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 6-35 months.

Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains in subjects aged 6-35 months.

Secondary: Number of subjects aged 6-35 months reporting fever ≥38ºC after Dose 1 and after Dose 2.

Secondary: Number of subjects aged 6-35 months reporting fever ≥38ºC after Dose 1 and after Dose 2.

Secondary: Number of subjects aged 6-35 months reporting solicited local adverse events (AEs).

Secondary: Number of subjects aged 6-35 months reporting solicited local adverse events (AEs).

Secondary: Number of subjects aged 6 months to <5 years, reporting fever ≥38ºC (100.4°F) and >39.0°C (102.2ºF) across doses.