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Clinical Trial Results:
A phase III, randomized, open-label, multicentre clinical trial to assess the immunogenicity and safety of GSK Biologicals’ Herpes Zoster vaccine GSK1437173A when co-administered with GSK Biologicals’ quadrivalent influenza vaccine FLU-D-QIV (GSK2321138A) versus separate administration of the two vaccines in adults aged 50 years and older.

Summary
EudraCT number	2013-000372-15
Trial protocol	DE
Global end of trial date	20 Mar 2015

Results information
Results version number	v2(current)
This version publication date	11 Oct 2020
First version publication date	02 Apr 2016
Other versions	v1
Version creation reason	Correction of full data set Results have been amended to account for consistency with other registries.

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

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Trial information

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Sponsor protocol code

117036

ISRCTN number

US NCT number

NCT01954251

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

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

Public contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, 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?

Analysis stage

Final

Date of interim/final analysis

20 Mar 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Mar 2015

Global end of trial reached?

Yes

Global end of trial date

20 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate the vaccine response rate (VRR) to the HZ/su vaccine (based on the humoral immune response) one month after the last vaccine dose in the HZ/su-FLU-D-QIV co-administration group. To demonstrate non-inferiority in terms of humoral immune response of two doses of the HZ/su vaccine when FLU-D-QIV vaccine is co-administered with the first HZ/su vaccine dose compared to two doses of HZ/su vaccine given alone, one month after the last vaccine dose. To demonstrate non-inferiority (in terms of HI antibody Geometric mean titres (GMTs)) of one dose of FLU-D-QIV vaccine when co-administered with the first HZ/su vaccine dose compared to one dose of FLU-D-QIV vaccine given alone, for the four strains included in FLU-D-QIV vaccine, at Day 21 post vaccination.

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 30 days after the last vaccination/product administration.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 565

Country: Number of subjects enrolled

Canada: 132

Country: Number of subjects enrolled

United States: 132

Worldwide total number of subjects

829

EEA total number of subjects

565

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)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

491

From 65 to 84 years

331

85 years and over

Subject disposition

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Recruitment details

Screening details

Out of the 829 subjects enrolled in this trial, 1 subject did not receive vaccination even though subject number had been allocated, hence he/she was excluded from study start.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

GSK1437173A + GSK2321138A Group

Arm description

The subjects assigned to the Co-Ad group received one injection of the FLU-D-QIV vaccine and one injection of the HZ/su study vaccine during the first visit and a second injection of the HZ/su study vaccine during the third visit, two months later.

Arm type

Experimental

Investigational medicinal product name

Herpes Zoster vaccine GSK 1437173A

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

2 doses administered intramuscularly (IM) in the deltoid region of the non-dominant arm.

Investigational medicinal product name

GSK Biologicals’ quadrivalent seasonal influenza vaccine FLU-D-QIV GSK2321138A

Investigational medicinal product code

Other name

Influsplit™ Tetra (Germany); Fluarix™ Quadrivalent (United States)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

2 doses administered intramuscularly (IM) in the deltoid region of the dominant arm.

Control Group

Arm description

The subjects assigned to the Control group received all vaccines separately: one injection of the FLU-D-QIV vaccine at the first visit, one injection of the HZ/su study vaccine at the third visit and a second injection of the HZ/su study vaccine at the fourth visit, all two months apart.

Arm type

Active comparator

Investigational medicinal product name

Herpes Zoster vaccine GSK 1437173A

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

2 doses administered intramuscularly (IM) in the deltoid region of the non-dominant arm.

Investigational medicinal product name

GSK Biologicals’ quadrivalent seasonal influenza vaccine FLU-D-QIV GSK2321138A

Investigational medicinal product code

Other name

Influsplit™ Tetra (Germany); Fluarix™ Quadrivalent (United States)

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

2 doses administered intramuscularly (IM) in the deltoid region of the dominant arm.

Number of subjects in period 1 ^[1]	GSK1437173A + GSK2321138A Group	Control Group
Started	413	415
Completed	400	396
Not completed	13	19
Adverse event, serious fatal	4	5
Consent withdrawn by subject	2	6
Adverse event, non-fatal	1	2
Lost to follow-up	6	6

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: Out of the 829 subjects enrolled in this trial, 1 subject did not receive vaccination even though subject number had been allocated, hence he/she was excluded from study start.

Baseline characteristics

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Reporting group title

GSK1437173A + GSK2321138A Group

Reporting group description

Reporting group title

Control Group

Reporting group description

Reporting group values	GSK1437173A + GSK2321138A Group	Control Group	Total
Number of subjects	413	415	828
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	63.4 ( 8.3 )	63.4 ( 8.8 )	-
Gender categorical
Units: Subjects
Female	211	218	429
Male	202	197	399

End points

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Reporting group title

GSK1437173A + GSK2321138A Group

Reporting group description

Reporting group title

Control Group

Reporting group description

Primary: Number of subjects with vaccine response to anti-gE antibodies

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End point title

Number of subjects with vaccine response to anti-gE antibodies ^[1] ^[2]

End point description

The vaccine response (VRR) for anti-gE humoral immunogenicity, as determined by enzyme-linked immunosorbent assay (ELISA),was assessed only in subjects from the GSK1437173A + GSK2321138A Group. The VRR for anti-gE was defined as the percentage of subjects who had at least: a 4-fold increase in the post-dose 2 anti-gE antibody concentration as compared to the pre-vaccination anti-gE antibody concentration, for subjects who were seropositive at baseline (cut-off ≥ 97 mIU/ml), or, a 4-fold increase in the post dose 2 anti-gE antibody concentrations as compared to the anti-gE antibodies cut-off value for seropositivity, for subjects who were seronegative at baseline (cut-off < 97 mIU/ml).

End point type

Primary

End point timeframe

At one month post-dose 2 (Month 3)

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: This outcome was descriptive, hence no statistical analyses were required.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	GSK1437173A + GSK2321138A Group
Number of subjects analysed	382
Units: Subjects	366

No statistical analyses for this end point

Primary: Vaccine response for anti-gE humoral immunogenicity

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End point title

Vaccine response for anti-gE humoral immunogenicity ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

At one month post-dose 2 (Month 3)

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: This outcome was descriptive, hence no statistical analyses were required.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	GSK1437173A + GSK2321138A Group
Number of subjects analysed	382
Units: Percentage
number (confidence interval 95%)	95.8 (93.3 to 97.6)

No statistical analyses for this end point

Primary: Adjusted geometric mean ELISA concentrations of anti-gE antibodies

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End point title

Adjusted geometric mean ELISA concentrations of anti-gE antibodies

End point description

Geometric means (GMs) of post-vaccination concentrations (Month 3 for GSK1437173A + GSK2321138A group and Month 5 for Control group) was calculated conditionally to the means of the pre-vaccination log-transformed concentrations for anti-gE (Month 0 for GSK1437173A + GSK2321138A group and Month 2 for Control group). Adjusted Least Squares (LS) means and difference of LS means between the groups were calculated together with 2-sided 95% CIs and back-transformed to the original units to provide GMCs.

End point type

Primary

End point timeframe

At one month post-dose 2 (Month 3 for GSK1437173A + GSK2321138A group and Month 5 for Control group)

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	382	388
Units: mIU/mL
geometric mean (confidence interval 95%)	52151.6 (48356 to 56245.2)	56247.4 (52177.3 to 60634.9)

Adjusted GMC rate 1 of anti-gE antibodies

Statistical analysis description

Adjusted ratios of Control group over GSK1437173A + GSK2321138A group in anti-gE antibody ELISA concentrations GMCs at one month after last vaccine dose. An Analysis of Covariance (ANCOVA) model was used to analyse post-vaccination log-transformed concentrations of anti-gE. The fixed-effect model included the minimisation variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate.

Comparison groups

GSK1437173A + GSK2321138A Group v Control Group

Number of subjects included in analysis

770

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

ANCOVA

Parameter type

Adjusted Geometric mean concentration

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.2

Notes
[5] - Comparison at one month after the last dose of HZ/su was performed between the Control group and GSK1437173A + GSK2321138A group. The GSK1437173A + GSK2321138A group was considered as statistically significant non-inferior compared to the Control group in terms of immunogenicity if the UL of the 2-sided 95% CI of the ratio of GMs between the Control and the Co-Ad group (Control over GSK1437173A + GSK2321138A) was below 1.5.

Primary: FLU Haemagglutination inhibition (HI) antibodies titers

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End point title

FLU Haemagglutination inhibition (HI) antibodies titers

End point description

For each strain included in the FLU-D-QIV vaccine, an ANOVA model was used to analyze post-vaccination log-transformed titers. The fixed-effect model included the minimization variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate. Geometric Means (GM) of post-vaccination titers (Day 21) were calculated conditionally to the means of the pre-vaccination log-transformed titers (Month 0) for each strain. Adjusted GMTs (GMTs adjusted for baseline titers) and Adjusted GMT ratios were calculated together with 2-sided 95% CIs.

End point type

Primary

End point timeframe

At Day 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	384	394
Units: Titers
geometric mean (confidence interval 95%)
Flu A/California/7/2009 H1N1 HI Day 21	187.5 (166.7 to 210.8)	194.3 (173 to 218.1)
Flu A/Texas/50/2012 H3N2 HI Day 21	63.7 (58.3 to 69.7)	65.9 (60.3 to 72)
Flu B/Brisbane/60/2008 Victoria HI Day 21	170.2 (156.1 to 185.6)	181.6 (166.7 to 197.8)
Flu B/Massachusetts/2/2012 Yamagata HI Day 21	423.5 (392 to 457.5)	413.9 (383.4 to 446.8)

Adjusted GMT ratio 1 of HI antibodies

Statistical analysis description

For the Flu A/California/7/2009 H1N1 strain ,an ANOVA model was used to analyze post-vaccination log-transformed titers. The fixed-effect model included the minimization variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate. GMs of post-vaccination titers (Day 21) were calculated conditionally to the means of the pre-vaccination log-transformed titers (Month 0) for this strain.

Comparison groups

GSK1437173A + GSK2321138A Group v Control Group

Number of subjects included in analysis

778

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

ANOVA

Parameter type

Adjusted geometric mean Titer ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.22

Notes
[6] - Comparisons at Day 21 after the FLU-D-QIV dose were performed between the Control group and GSK1437173A + GSK2321138A group. The GSK1437173A + GSK2321138A group was considered as statistically significant non inferior compared to the Control group in terms of immunogenicity (for each strain) if the UL of 2-sided 95% CI of the ratio of GMTs between the Control and the GSK1437173A + GSK2321138A (Control/ GSK1437173A + GSK2321138A) group is below 1.5.

Adjusted GMT ratio 2 of HI antibodies

Statistical analysis description

For the Flu A/Texas/50/2012 H3N2 strain ,an ANOVA model was used to analyze post-vaccination log-transformed titers. The fixed-effect model included the minimization variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate. GMs of post-vaccination titers (Day 21) were calculated conditionally to the means of the pre-vaccination log-transformed titers (Month 0) for this strain.

Comparison groups

GSK1437173A + GSK2321138A Group v Control Group

Number of subjects included in analysis

778

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

ANOVA

Parameter type

Adjusted geometric mean Titer ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.17

Notes
[7] - Comparisons at Day 21 after the FLU-D-QIV dose were performed between the Control group and GSK1437173A + GSK2321138A group. The GSK1437173A + GSK2321138A group was considered as statistically significant non inferior compared to the Control group in terms of immunogenicity (for each strain) if the UL of 2-sided 95% CI of the ratio of GMTs between the Control and the GSK1437173A + GSK2321138A (Control/ GSK1437173A + GSK2321138A) group is below 1.5.

Adjusted GMT ratio 3 of HI antibodies

Statistical analysis description

For the Flu B/Brisbane/60/2008 Victoria strain ,an ANOVA model was used to analyze post-vaccination log-transformed titers. The fixed-effect model included the minimization variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate. GMs of post-vaccination titers (Day 21) were calculated conditionally to the means of the pre-vaccination log-transformed titers (Month 0) for this strain.

Comparison groups

GSK1437173A + GSK2321138A Group v Control Group

Number of subjects included in analysis

778

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

ANOVA

Parameter type

Adjusted geometric mean Titer ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.2

Notes
[8] - Comparisons at Day 21 after the FLU-D-QIV dose were performed between the Control group and GSK1437173A + GSK2321138A group. The GSK1437173A + GSK2321138A group was considered as statistically significant non inferior compared to the Control group in terms of immunogenicity (for each strain) if the UL of 2-sided 95% CI of the ratio of GMTs between the Control and the GSK1437173A + GSK2321138A (Control/ GSK1437173A + GSK2321138A) group is below 1.5.

Adjusted GMT ratio 4 of HI antibodies

Statistical analysis description

For the Flu B/Massachusetts/2/2012 Yamagata strain ,an ANOVA model was used to analyze post-vaccination log-transformed titers. The fixed-effect model included the minimization variable (age cohorts) and the treatment as fixed effect. The pre-vaccination log-transformed concentrations were included as continuous covariate. GMs of post-vaccination titers (Day 21) were calculated conditionally to the means of the pre-vaccination log-transformed titers (Month 0) for this strain.

Comparison groups

Control Group v GSK1437173A + GSK2321138A Group

Number of subjects included in analysis

778

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

ANOVA

Parameter type

Adjusted geometric mean Titer ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.09

Notes
[9] - Comparisons at Day 21 after the FLU-D-QIV dose were performed between the Control group and GSK1437173A + GSK2321138A group. The GSK1437173A + GSK2321138A group was considered as statistically significant non inferior compared to the Control group in terms of immunogenicity (for each strain) if the UL of 2-sided 95% CI of the ratio of GMTs between the Control and the GSK1437173A + GSK2321138A (Control/ GSK1437173A + GSK2321138A) group is below 1.5.

Secondary: Number of subjects with FLU HI antibodies ≥1:10

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End point title

Number of subjects with FLU HI antibodies ≥1:10

End point description

FLU HI antibodies were assessed in four strains: Flu A/California/7/2009 H1N1, Flu A/Texas/50/2012 H3N2, Flu B/Brisbane/60/2008 Victoria and Flu B/Massachusetts/2/2012 Yamagata (Yamag). Cut-off titer for seropositivity was 1:10.

End point type

Secondary

End point timeframe

At Days 0 (PRE) and 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	386	395
Units: Subjects
Flu A/California/7/2009 H1N1 Day 0 [N=386,395]	288	294
Flu A/California/7/2009 H1N1Day 21 [N=384,394]	381	389
Flu A/Texas/50/2012 H3N2 Day 0 [N=386,395]	283	300
Flu A/Texas/50/2012 H3N2 Day 21 [N=384,394]	380	392
Flu B/Brisbane/60/2008 Victoria Day 0 [N=386,395]	365	375
Flu B/Brisbane/60/2008 Victoria Day 21 [N=384,394]	383	394
Flu B/Massachusetts/2/2012 Yamag Day 0 [N=386,395]	376	389
Flu B/Massachusetts/2/2012 Yamag Day21 [N=384,394]	384	394

No statistical analyses for this end point

Secondary: Number of seroprotected subjects with HI antibody concentrations ≥ 1:40

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End point title

Number of seroprotected subjects with HI antibody concentrations ≥ 1:40

End point description

Seroprotection rate is defined as the percentage of vaccines with a serum HI titer ≥1:40 that usually was accepted as indicating protection.

End point type

Secondary

End point timeframe

At Day 0 (PRE) and at Day 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	386	395
Units: Subjects
Flu A/California/7/2009 H1N1 HI Day 0 [N=386,395]	185	161
Flu A/California/7/2009 H1N1 HI Day 21 [N=384,394]	347	360
Flu A/Texas/50/2012 H3N2 HI Day 0 [N=386,395]	134	121
Flu A/Texas/50/2012 H3N2 HI Day 21 [N=384,394]	292	295
Flu B/Brisbane/60/2008 Vic HI Day 0 [N=386,395]	279	271
Flu B/Brisbane/60/2008 Vic HI Day 21 [N=384,394]	372	382
Flu B/Massach/2/2012 Yama HI Day 0 [N=386,395]	351	361
Flu B/Massach/2/2012 Yama HI Day 21 [N=384,394]	383	393

No statistical analyses for this end point

Secondary: FLU Haemagglutination inhibition (HI) antibody titers

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End point title

FLU Haemagglutination inhibition (HI) antibody titers

End point description

HI antibody titres against the four influenza vaccine strains Flu A/California/7/2009, Flu A/Texas/50/2012, Flu B/Brisbane/60/2008 Victoria and Flu B/Massachusetts/2/2012 Yamagata were expressed as geometric mean titers (GMTs).

End point type

Secondary

End point timeframe

At Day 0 (PRE) and Day 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	386	395
Units: Titers
geometric mean (confidence interval 95%)
Flu A/California/7/2009 H1N1 HI Day 0	29 (25.1 to 33.5)	24.9 (21.8 to 28.5)
Flu A/California/7/2009 H1N1 HI Day 21	196.2 (172.2 to 223.5)	193.2 (170.2 to 219.4)
Flu A/Texas/50/2012 H3N2 HI Day 0	19.6 (17.5 to 21.9)	19 (17.1 to 21.1)
Flu A/Texas/50/2012 H3N2 HI Day 21	65.4 (59 to 72.5)	66.8 (60.4 to 74)
Flu B/Brisbane/60/2008 Victoria HI Day 0	52.2 (46.9 to 58.1)	48.6 (43.7 to 54)
Flu B/Brisbane/60/2008 Victoria HI Day 21	177.2 (161.6 to 194.2)	185.2 (168 to 204.1)
Flu B/Massachusetts/2/2012 Yamagata HI Day 0	128.8 (115.7 to 143.4)	127 (114.9 to 140.3)
Flu B/Massachusetts/2/2012 Yamagata HI Day 21	433.7 (401.3 to 468.7)	423.3 (388 to 461.8)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects in terms of HI antibodies

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End point title

Number of seroconverted subjects in terms of HI antibodies

End point description

The number of seroconverted subjects was assessed in terms of HI antibodies against the four influenza vaccine strains Flu A/California/7/2009, Flu A/Texas/50/2012, Flu B/Brisbane/60/2008 Victoria and Flu B/Massachusetts/2/2012 Yamagata.

End point type

Secondary

End point timeframe

At Day 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	384	394
Units: Subjects
Flu A/California/7/2009 H1N1 HI	232	240
Flu A/Texas/50/2012 H3N2 HI	136	139
Flu B/Brisbane/60/2008 Victoria HI	143	169
Flu B/Massachusetts/2/2012 Yamagata HI	154	148

No statistical analyses for this end point

Secondary: Geometric mean ratio for Flu HI antibodies post-vaccination titer

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End point title

Geometric mean ratio for Flu HI antibodies post-vaccination titer

End point description

The geometric mean ratio for Flu HI antibodies against the four influenza vaccine strains Flu A/California/7/2009, Flu A/Texas/50/2012, Flu B/Brisbane/60/2008 Victoria and Flu B/Massachusetts/2/2012 Yamagata was defined as the geometric mean of the within subject ratios of the post-vaccination reciprocal HI titer to the Day 0 reciprocal HI titer.

End point type

Secondary

End point timeframe

At Day 21 post vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	384	394
Units: Ratio
geometric mean (confidence interval 95%)
Flu A/California/7/2009 H1N1 HI	6.8 (5.9 to 7.8)	7.7 (6.7 to 9)
Flu A/Texas/50/2012 H3N2 HI	3.4 (3 to 3.7)	3.5 (3.2 to 4)
Flu B/Brisbane/60/2008 Victoria HI	3.4 (3 to 3.8)	3.8 (3.4 to 4.3)
Flu B/Massachusetts/2/2012 Yamagata HI	3.4 (3 to 3.7)	3.3 (3 to 3.7)

No statistical analyses for this end point

Secondary: Number of subjects with solicited local symptoms

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End point title

Number of subjects with solicited local symptoms ^[10]

End point description

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. Relationship analysis was not performed. Since this group only received GSK2321138A vaccine at Dose 1 (D1) and GSK1437173A vaccine at Dose 1 and Dose 2 (D2), only the results for the respective doses and vaccine administrations were available.

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) after each vaccine dose

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	GSK1437173A + GSK2321138A Group
Number of subjects analysed	410
Units: Subjects
Any Pain D1 GSK 2321138A [N=410]	140
Grade3 Pain D1 GSK 2321138A [N=410]	7
Any Redness D1 GSK 2321138A [N=410]	31
Grade3 Redness D1 GSK 2321138A [N=410]	1
Any Swelling D1 GSK 2321138A [N=410]	16
Grade3 Swelling D1 GSK 2321138A [N=410]	0
Any Pain D1 GSK 1437173A [N=410]	292
Grade3 Pain D1 GSK 1437173A [N=410]	31
Any Redness D1 GSK 1437173A [N=410]	112
Grade3 Redness D1 GSK 1437173A [N=410]	4
Any Swelling D1 GSK 1437173A [N=410]	64
Grade3 Swelling D1 GSK 1437173A [N=410]	0
Any Pain D2 GSK 1437173A [N=403]	290
Grade3 Pain D2 GSK 1437173A [N=403]	32
Any Redness D2 GSK 1437173A [N=403]	103
Grade3 Redness D2 GSK 1437173A [N=403]	5
Any Swelling D2 GSK 1437173A [N=403]	64
Grade3 Swelling D2 GSK 1437173A [N=403]	0

No statistical analyses for this end point

Secondary: Number of subjects with solicited local symptoms

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End point title

Number of subjects with solicited local symptoms ^[11]

End point description

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) after each vaccine dose

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	Control Group
Number of subjects analysed	412
Units: Subjects
Any Pain, Dose 1 [N=412]	112
Grade 3 Pain, Dose 1 [N=412]	4
Any Redness, Dose 1 [N=412]	37
Grade 3 Redness, Dose 1 [N=412]	2
Any Swelling, Dose 1 [N=412]	18
Grade 3 Swelling, Dose 1 [N=412]	1
Any Pain, Dose 2 [N=405]	280
Grade 3 Pain, Dose 2 [N=405]	25
Any Redness, Dose 2 [N=405]	91
Grade 3 Redness, Dose 2 [N=405]	6
Any Swelling, Dose 2 [N=405]	47
Grade 3 Swelling, Dose 2 [N=405]	0
Any Pain, Dose 3 [N=402]	269
Grade 3 Pain, Dose 3 [N=402]	25
Any Redness, Dose 3 [N=402]	100
Grade 3 Redness, Dose 3 [N=402]	7
Any Swelling, Dose 3 [N=402]	50
Grade 3 Swelling, Dose 3 [N=402]	4

No statistical analyses for this end point

Secondary: Number of subjects with solicited local symptoms

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End point title

Number of subjects with solicited local symptoms

End point description

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) across doses

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	411	413
Units: Subjects
Any Pain Across Doses	344	318
Grade 3 Pain Across Doses	55	40
Any Redness Across Doses	153	144
Grade 3 Redness Across Doses	9	14
Any Swelling Across Doses	99	86
Grade 3 Swelling Across Doses	0	5

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms

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End point title

Number of subjects with solicited general symptoms ^[12]

End point description

Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, shivering and fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) after each vaccine dose

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	GSK1437173A + GSK2321138A Group
Number of subjects analysed	409
Units: Subjects
Any Arthralgia Dose 1 [N=409]	89
Grade 3 Arthralgia Dose 1 [N=409]	8
Related Arthralgia Dose 1 [N=409]	67
Any Fatigue Dose 1 [N=409]	150
Grade 3 Fatigue Dose 1 [N=409]	15
Related Fatigue Dose 1 [N=409]	107
Any Gastrointestinal Dose 1 [N=409]	57
Grade 3 Gastrointestinal Dose 1 [N=409]	5
Related Gastrointestinal Dose 1 [N=409]	28
Any Headache Dose 1 [N=409]	122
Grade 3 Headache Dose 1 [N=409]	5
Related Headache Dose 1 [N=409]	80
Any Myalgia Dose 1 [N=409]	135
Grade 3 Myalgia Dose 1 [N=409]	11
Related Myalgia Dose 1 [N=409]	105
Any Shivering Dose 1 [N=409]	101
Grade 3 Shivering Dose 1 [N=409]	12
Related Shivering Dose 1 [N=409]	86
Any Temperature Dose 1 [N=409]	63
Grade 3 Temperature Dose 1 [N=409]	1
Related Temperature Dose 1 [N=409]	53
Any Arthralgia Dose 2 [N=402]	114
Grade 3 Arthralgia Dose 2 [N=402]	16
Related Arthralgia Dose 2 [N=402]	94
Any Fatigue Dose 2 [N=402]	167
Grade 3 Fatigue Dose 2 [N=402]	23
Related Fatigue Dose 2 [N=402]	138
Any Gastrointestinal Dose 2 [N=402]	47
Grade 3 Gastrointestinal Dose 2 [N=402]	3
Related Gastrointestinal Dose 2 [N=402]	32
Any Headache Dose 2 [N=402]	136
Grade 3 Headache Dose 2 [N=402]	16
Related Headache Dose 2 [N=402]	109
Any Myalgia Dose 2 [N=402]	157
Grade 3 Myalgia Dose 2 [N=402]	18
Related Myalgia Dose 2 [N=402]	135
Any Shivering Dose 2 [N=402]	142
Grade 3 Shivering Dose 2 [N=402]	30
Related Shivering Dose 2 [N=402]	122
Any Temperature Dose 2 [N=402]	74
Grade 3 Temperature Dose 2 [N=402]	1
Related Temperature Dose 2 [N=402]	63

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms

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End point title

Number of subjects with solicited general symptoms ^[13]

End point description

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) after each vaccine dose

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome was descriptive, hence no statistical analyses were required.

End point values	Control Group
Number of subjects analysed	411
Units: Subjects
Any Arthralgia, Dose 1 [N=411]	37
Grade 3 Arthralgia, Dose 1 [N=411]	8
Related Arthralgia, Dose 1 [N=411]	25
Any Fatigue, Dose 1 [N=411]	52
Grade 3 Fatigue, Dose 1 [N=411]	4
Related Fatigue, Dose 1 [N=411]	33
Any Gastrointestinal, Dose 1 [N=411]	32
Grade 3 Gastrointestinal, Dose 1 [N=411]	2
Related Gastrointestinal, Dose 1 [N=411]	16
Any Headache, Dose 1 [N=411]	57
Grade 3 Headache, Dose 1 [N=411]	2
Related Headache, Dose 1 [N=411]	31
Any Myalgia, Dose 1 [N=411]	55
Grade 3 Myalgia, Dose 1 [N=411]	4
Related Myalgia, Dose 1 [N=411]	45
Any Shivering, Dose 1 [N=411]	30
Grade 3 Shivering, Dose 1 [N=411]	0
Related Shivering, Dose 1 [N=411]	25
Any Temperature, Dose 1 [N=411]	18
Grade 3 Temperature, Dose 1 [N=411]	0
Related Temperature, Dose 1 [N=411]	15
Any Arthralgia, Dose 2 [N=405]	67
Grade 3 Arthralgia, Dose 2 [N=405]	6
Related Arthralgia, Dose 2 [N=405]	51
Any Fatigue, Dose 2 [N=405]	108
Grade 3 Fatigue, Dose 2 [N=405]	9
Related Fatigue, Dose 2 [N=405]	87
Any Gastrointestinal, Dose 2 [N=405]	37
Grade 3 Gastrointestinal, Dose 2 [N=405]	1
Related Gastrointestinal, Dose 2 [N=405]	28
Any Headache, Dose 2 [N=405]	87
Grade 3 Headache, Dose 2 [N=405]	8
Related Headache, Dose 2 [N=405]	70
Any Myalgia, Dose 2 [N=405]	135
Grade 3 Myalgia, Dose 2 [N=405]	7
Related Myalgia, Dose 2 [N=405]	115
Any Shivering, Dose 2 [N=405]	87
Grade 3 Shivering, Dose 2 [N=405]	10
Related Shivering, Dose 2 [N=405]	75
Any Temperature, Dose 2 [N=405]	44
Grade 3 Temperature, Dose 2 [N=405]	1
Related Temperature, Dose 2 [N=405]	34
Any Arthralgia, Dose 3 [N=402]	95
Grade 3 Arthralgia, Dose 3 [N=402]	18
Related Arthralgia, Dose 3 [N=402]	79
Any Fatigue, Dose 3 [N=402]	149
Grade 3 Fatigue, Dose 3 [N=402]	31
Related Fatigue, Dose 3 [N=402]	120
Any Gastrointestinal, Dose 3 [N=402]	63
Grade 3 Gastrointestinal, Dose 3 [N=402]	6
Related Gastrointestinal, Dose 3 [N=402]	46
Any Headache, Dose 3 [N=402]	133
Grade 3 Headache, Dose 3 [N=402]	23
Related Headache, Dose 3 [N=402]	111
Any Myalgia, Dose 3 [N=402]	138
Grade 3 Myalgia, Dose 3 [N=402]	24
Related Myalgia, Dose 3 [N=402]	121
Any Shivering, Dose 3 [N=402]	147
Grade 3 Shivering, Dose 3 [N=402]	23
Related Shivering, Dose 3 [N=402]	131
Any Temperature, Dose 3 [N=402]	87
Grade 3 Temperature, Dose 3 [N=402]	2
Related Temperature, Dose 3 [N=402]	70

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms

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End point title

Number of subjects with solicited general symptoms

End point description

End point type

Secondary

End point timeframe

Within 7 days (Days 0-6) across doses

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	411	413
Units: Subjects
Any Arthralgia, Across Doses	154	135
Grade 3 Arthralgia, Across Doses	23	24
Related Arthralgia, Across Doses	121	110
Any Fatigue, Across Doses	224	186
Grade 3 Fatigue, Across Doses	30	38
Related Fatigue, Across Doses	175	151
Any Gastrointestinal, Across Doses	90	92
Grade 3 Gastrointestinal, Across Doses	6	9
Related Gastrointestinal, Across Doses	49	66
Any Headache, Across Doses	183	170
Grade 3 Headache, Across Doses	20	28
Related Headache, Across Doses	140	142
Any Myalgia, Across Doses	201	201
Grade 3 Myalgia, Across Doses	27	30
Related Myalgia, Across Doses	167	177
Any Shivering, Across Doses	174	181
Grade 3 Shivering, Across Doses	35	30
Related Shivering, Across Doses	151	159
Any Temperature, Across Doses	107	119
Grade 3 Temperature, Across Doses	2	3
Related Temperature, Across Doses	90	96

No statistical analyses for this end point

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

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End point title

Number of subjects with unsolicited adverse events (AEs)

End point description

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination.

End point type

Secondary

End point timeframe

During 30 days (Days 0-29) after vaccination

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	413	415
Units: Subjects
Any AEs	110	162
Grade 3 AEs	17	29
Related AEs	18	26

No statistical analyses for this end point

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

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End point title

Number of subjects with serious adverse events (SAEs)

End point description

Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

End point type

Secondary

End point timeframe

From first vaccination up to Month 18 (study end)

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	413	415
Units: Subjects
Any SAEs	42	39

No statistical analyses for this end point

Secondary: Number of subjects with potential immune-mediated diseases (pIMDs)

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End point title

Number of subjects with potential immune-mediated diseases (pIMDs)

End point description

pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

End point type

Secondary

End point timeframe

From first vaccination up to Month 18 (study end)

End point values	GSK1437173A + GSK2321138A Group	Control Group
Number of subjects analysed	413	415
Units: Subjects
Any pIMDs	4	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Systematically-assessed symptoms: Days 0-7 post each vaccine dose; AEs: Days 0-29 post each vaccine dose; SAEs: from Day 0 to Month 18

Adverse event reporting additional description

The occurrence of reported AEs (all/related) was not available and encoded as equal to the number of subjects affected. GSK1437173A + GSK2321138A Group: for 1 subject myasthenia gravis became an SAE; The Psychotic disorder was renamed Depression; Control Group: initial worsening of hiatal hernia for 1 subject was not considered an SAE.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

GSK1437173A + GSK2321138A Group

Reporting group description

Reporting group title

Control Group

Reporting group description

Serious adverse events	GSK1437173A + GSK2321138A Group	Control Group
Total subjects affected by serious adverse events
subjects affected / exposed	42 / 413 (10.17%)	39 / 415 (9.40%)
number of deaths (all causes)	3	5
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Adrenal adenoma
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic cancer metastatic
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lung adenocarcinoma metastatic
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 413 (0.24%)	2 / 415 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death (unknown causes)
subjects affected / exposed	0 / 413 (0.00%)	2 / 415 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Asthenia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic lung injury
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Coronary artery disease
subjects affected / exposed	3 / 413 (0.73%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 413 (0.24%)	2 / 415 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	2 / 413 (0.48%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Aortic valve stenosis
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	3 / 413 (0.73%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 413 (0.48%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acquired syringomyelia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain stem infarction
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dementia
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myasthenia gravis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Occipital neuralgia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Hypochromic anaemia
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vestibular disorder
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Blindness
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Intestinal obstruction
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 413 (0.00%)	2 / 415 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Calculus urethral
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 413 (0.24%)	3 / 415 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 413 (0.24%)	2 / 415 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal discomfort
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	3 / 413 (0.73%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 413 (0.24%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 413 (0.48%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Abscess
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cellulitis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis pharyngeal
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 413 (0.24%)	0 / 415 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 413 (0.00%)	1 / 415 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	GSK1437173A + GSK2321138A Group	Control Group
Total subjects affected by non serious adverse events
subjects affected / exposed	370 / 413 (89.59%)	369 / 415 (88.92%)
General disorders and administration site conditions
Pain
alternative assessment type: Systematic
subjects affected / exposed ^[1]	344 / 411 (83.70%)	318 / 413 (77.00%)
occurrences all number	344	318
Redness
alternative assessment type: Systematic
subjects affected / exposed ^[2]	153 / 411 (37.23%)	144 / 413 (34.87%)
occurrences all number	153	144
Swelling
alternative assessment type: Systematic
subjects affected / exposed ^[3]	99 / 411 (24.09%)	86 / 413 (20.82%)
occurrences all number	99	86
Arthralgia
subjects affected / exposed ^[4]	154 / 411 (37.47%)	135 / 413 (32.69%)
occurrences all number	154	135
Fatigue
alternative assessment type: Systematic
subjects affected / exposed ^[5]	224 / 411 (54.50%)	186 / 413 (45.04%)
occurrences all number	224	186
Gastrointestinal
alternative assessment type: Systematic
subjects affected / exposed ^[6]	90 / 411 (21.90%)	92 / 413 (22.28%)
occurrences all number	90	92
Headache
alternative assessment type: Systematic
subjects affected / exposed ^[7]	183 / 411 (44.53%)	170 / 413 (41.16%)
occurrences all number	183	170
Myalgia
alternative assessment type: Systematic
subjects affected / exposed ^[8]	201 / 411 (48.91%)	201 / 413 (48.67%)
occurrences all number	201	201
Shivering
alternative assessment type: Systematic
subjects affected / exposed ^[9]	174 / 411 (42.34%)	181 / 413 (43.83%)
occurrences all number	174	181
Temperature/(Oral)
alternative assessment type: Systematic
subjects affected / exposed ^[10]	107 / 411 (26.03%)	119 / 413 (28.81%)
occurrences all number	107	119
Infections and infestations
Nasopharyngitis
subjects affected / exposed	14 / 413 (3.39%)	22 / 415 (5.30%)
occurrences all number	14	22

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This analysis was based only on those subjects from the Total Vaccinated cohort who completed symptom sheets.

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Were there any global substantial amendments to the protocol? Yes

03 Jul 2013

Amendment 1 Addressing a request from the US Food and Drug Administration Center for Biologics Evaluation and Research (CBER), a secondary objective has been added for an evaluation of the difference between the Seroconversion Rates (SCR) for each influenza strain when administered either concomitantly with or separately from the HZ/su vaccine. Following CBER’s recommendation, the upper limit of the two-sided 95% Confidence Interval (CI) between the SCR of each strain should not exceed 10%. As a consequence, the sample size has been increased in order to ensure adequate power for this additional secondary objective. The overall power to reach the co-primary objectives has been corrected with the new sample size determination. As per CBER’s request, it was added in the secondary objective that the immunogenicity of the FLU-D-QIV vaccine will be assessed according to the CBER criteria for determination of immunogenicity (SCR and SPR) as described in Section III, B1b-FDA Guidance to Industry, Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines, May 2007. The nominal powers have been calculated in order to respond to this request, assuming 393 subjects are available in each arm. As per CBER’s request, Section 6.5 has been amended to indicate that any medical condition including the occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the opinion of the investigator, exposes the subject to unacceptable risk from subsequent vaccination, constitutes absolute contraindications to further administration of HZ/su vaccine. The change is not in response to any safety concern identified by GSK arising from an event or series of events in any completed or ongoing clinical studies that have been or are being conducted as part of GSK’s Zoster vaccine program.

16 May 2014

Amendment 2 The cut-off of the gE-specific ELISA assay has been changed from 18 to 97 mIU/mL. Background signal has been measured with the anti-gE ELISA on samples from Varicella Zoster Virus (VZV) naïve paediatric subjects. This observation of background signal on VZV naïve samples was not part of the original validation of the assay and establishment of the assay cut-off. Background signal measured with the anti-gE ELISA has no impact on Zoster project clinical conclusions as the vast majority of the samples (at all timepoints) have high titers well above the unspecific response level measured on VZV naïve samples from Measles, Mumps, Rubella and Varicella (MMRV) studies and Zoster vaccine responses are very robust. However this finding triggered re-evaluation of the assay cut-off. Based on complementary validation experiments performed in line with Clinical and Laboratory Standards Institute (CLSI) guidelines and taking into account internal company guidelines the technical and seropositivity cut-off has been set at 97 mIU/mL.

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.

The current data reflect the data reported in the database at the time of the end-of-study analysis. The previous data were based on the primary analysis including a safety analysis up to the data lock point of 7-APR-2015.

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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 with vaccine response to anti-gE antibodies

Primary: Number of subjects with vaccine response to anti-gE antibodies

Primary: Vaccine response for anti-gE humoral immunogenicity

Primary: Vaccine response for anti-gE humoral immunogenicity

Primary: Adjusted geometric mean ELISA concentrations of anti-gE antibodies

Primary: Adjusted geometric mean ELISA concentrations of anti-gE antibodies

Primary: FLU Haemagglutination inhibition (HI) antibodies titers

Primary: FLU Haemagglutination inhibition (HI) antibodies titers

Secondary: Number of subjects with FLU HI antibodies ≥1:10

Secondary: Number of subjects with FLU HI antibodies ≥1:10

Secondary: Number of seroprotected subjects with HI antibody concentrations ≥ 1:40

Secondary: Number of seroprotected subjects with HI antibody concentrations ≥ 1:40

Secondary: FLU Haemagglutination inhibition (HI) antibody titers

Secondary: FLU Haemagglutination inhibition (HI) antibody titers

Secondary: Number of seroconverted subjects in terms of HI antibodies

Secondary: Number of seroconverted subjects in terms of HI antibodies

Secondary: Geometric mean ratio for Flu HI antibodies post-vaccination titer

Secondary: Geometric mean ratio for Flu HI antibodies post-vaccination titer

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

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

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

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

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

Secondary: Number of subjects with potential immune-mediated diseases (pIMDs)

Secondary: Number of subjects with potential immune-mediated diseases (pIMDs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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