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Clinical Trial Results:
A Phase III Stratified, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety, Tolerability, and Immunogenicity of Two Doses of aH5N1 when Administered to Adult and Elderly Subjects With and Without Immunosuppressive Conditions.

Summary
EudraCT number	2011-003573-28
Trial protocol	IT
Global end of trial date	04 May 2015

Results information
Results version number	v1(current)
This version publication date	10 Oct 2018
First version publication date	10 Oct 2018
Other versions

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

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Trial information

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Sponsor protocol code

V87_26

ISRCTN number

US NCT number

NCT02107807

WHO universal trial number (UTN)

Sponsor organisation name

Seqirus

Sponsor organisation address

The Point, 29 Market Street, Maidenhead, United Kingdom,

Public contact

Clinical Trial Disclosure Manager, Seqirus, seqirus.clinicaltrials@seqirus.com

Scientific contact

Clinical Trial Disclosure Manager, Seqirus, seqirus.clinicaltrials@seqirus.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

02 Oct 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 May 2015

Was the trial ended prematurely?

Main objective of the trial

Primary Immunogenicity Objective To evaluate homologous antibody responses to aH5N1 vaccine 3 weeks after second vaccination (day 43) according to CHMP immunogenicity criteria in adult (18 through 60 years of age) and elderly (≥61 years of age) subjects who are healthy or with immunosuppressive conditions, as measured by hemagglutination inhibition (HI) assay Primary Safety Objective To evaluate in pooled age groups 18 years of age and older solicited and unsolicited adverse events in adults and elderly subjects who are healthy or with immunosuppressive conditions who have received aTIV or aH5N1 vaccine

Protection of trial subjects

This clinical study was designed, implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC and US CFR Title 21), the Sponsor’s codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations 1997, ICH 1997, Declaration of Helsinki).

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Apr 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 108

Country: Number of subjects enrolled

Italy: 289

Country: Number of subjects enrolled

Australia: 142

Worldwide total number of subjects

539

EEA total number of subjects

397

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)

373

From 65 to 84 years

162

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled from 15 sites in 3 countries: Australia (3 sites), Germany (4 sites), Italy (8 sites)

Screening details

All enrolled subjects were included in the trial

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

This is an observer-blind study. All vaccines were administered only by unblinded personnel who were qualified to perform that function under applicable local laws and regulations for the specific study site.

Are arms mutually exclusive

Yes

aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Arm description

Subjects ≥ 18 to ≤ 60 years of age with underlying immunosuppressive who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Monovalent MF59-adjuvanted A/H5N1 influenza vaccine (aH5N1)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Arm description

Subjects ≥ 18 to ≤ 60 years of age with immunosuppressive conditions who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Trivalent inactivated MF59-adjuvanted subunit influenza vaccine (aTIV)

Investigational medicinal product code

Other name

Fluad

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aH5N1, ≥ 18 to ≤ 60 years, healthy

Arm description

Healthy subjects ≥ 18 to ≤ 60 years of age who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Monovalent MF59-adjuvanted A/H5N1 influenza vaccine (aH5N1)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aTIV, ≥ 18 to ≤ 60 years/healthy

Arm description

Arm type

Experimental

Investigational medicinal product name

Trivalent inactivated MF59-adjuvanted subunit influenza vaccine (aTIV)

Investigational medicinal product code

Other name

Fluad

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aH5N1, ≥61 years/with immunosuppressive conditions

Arm description

Subjects ≥ 61 years of age with underlying immunosuppressive conditions who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Monovalent MF59-adjuvanted A/H5N1 influenza vaccine (aH5N1)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aTIV, ≥61 years/with immunosuppressive conditions

Arm description

Subjects ≥ 61 years of age with immunosuppressive conditions who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Trivalent inactivated MF59-adjuvanted subunit influenza vaccine (aTIV)

Investigational medicinal product code

Other name

Fluad

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aH5N1, ≥61 years/healthy

Arm description

Healthy subjects ≥ 61 years of age who provided immunogenicity data at Day 1 and Day 43. FAS for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay, homologous strain) at baseline (Day 1) and 3 weeks after (planned) second vaccination (Day 43). FAS for secondary (SRH) objective: All subjects in the All Enrolled Set who are randomized, received at least one study vaccination and provided immunogenicity data (SRH assay, homologous strain) at baseline (Day 1), 3 weeks after first vaccination (Day 22) and 3 weeks after (planned) second vaccination (Day 43) – FAS Secondary SRH.

Arm type

Experimental

Investigational medicinal product name

Monovalent MF59-adjuvanted A/H5N1 influenza vaccine (aH5N1)

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

aTIV, ≥61 years/healthy

Arm description

Arm type

Experimental

Investigational medicinal product name

Trivalent inactivated MF59-adjuvanted subunit influenza vaccine (aTIV)

Investigational medicinal product code

Other name

Fluad

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

2 IM injections administered 3 weeks apart to the deltoid muscle.

Number of subjects in period 1	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Started	149	31	58	33	148	31	62	27
Completed	144	29	58	31	141	29	59	25
Not completed	5	2	0	2	7	2	3	2
Adverse event, serious fatal	1	-	-	-	1	-	-	-
Consent withdrawn by subject	2	-	-	1	4	1	-	-
Adverse event, non-fatal	1	-	-	-	1	-	-	-
Other	-	1	-	-	-	-	-	-
Lost to follow-up	1	1	-	1	1	1	3	2

Baseline characteristics

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Reporting group title

aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aH5N1, ≥ 18 to ≤ 60 years, healthy

Reporting group description

Reporting group title

aTIV, ≥ 18 to ≤ 60 years/healthy

Reporting group description

Reporting group title

aH5N1, ≥61 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aTIV, ≥61 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aH5N1, ≥61 years/healthy

Reporting group description

Reporting group title

aTIV, ≥61 years/healthy

Reporting group description

Reporting group values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy	Total
Number of subjects	149	31	58	33	148	31	62	27	539
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	149	31	58	33	64	10	18	10	373
From 65-84 years	0	0	0	0	84	20	42	16	162
85 years and over	0	0	0	0	0	1	2	1	4
Age continuous
Units: years
arithmetic mean (standard deviation)	46.2 ± 8.85	44.5 ± 8.26	37.9 ± 12.87	38.1 ± 13.31	66.2 ± 4.74	67.4 ± 5.37	69.6 ± 7.04	68.6 ± 7.02	-
Gender categorical
Units: Subjects
Female	22	7	36	15	13	3	29	16	141
Male	127	24	22	18	135	28	33	11	398
Race
Units: Subjects
Asian	3	1	0	0	1	0	0	0	5
Black	6	3	1	1	1	1	0	0	13
Native Pacific Islander	2	0	0	0	0	0	0	0	2
White	136	27	57	32	142	30	62	27	513
Other	2	0	0	0	4	0	0	0	6
Ethnicity
Units: Subjects
Hispanic or Latino	9	4	2	0	4	0	0	0	19
Not Hispanic or Latino	140	27	56	33	144	31	59	26	516
Not reported	0	0	0	0	0	0	3	1	4
Unknown	0	0	0	0	0	0	0	0	0
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	77.2 ± 15.68	75.9 ± 11.86	70.2 ± 15.50	79.6 ± 19.89	78.1 ± 13.58	77.9 ± 12.84	79.8 ± 18.10	81.6 ± 18.18	-
BMI
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	25.0 ± 4.09	25.2 ± 4.09	24.6 ± 5.31	26.2 ± 5.41	26.3 ± 4.28	26.0 ± 4.03	27.6 ± 5.51	29.3 ± 7.40	-

End points

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Reporting group title

aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aH5N1, ≥ 18 to ≤ 60 years, healthy

Reporting group description

Reporting group title

aTIV, ≥ 18 to ≤ 60 years/healthy

Reporting group description

Reporting group title

aH5N1, ≥61 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aTIV, ≥61 years/with immunosuppressive conditions

Reporting group description

Reporting group title

aH5N1, ≥61 years/healthy

Reporting group description

Reporting group title

aTIV, ≥61 years/healthy

Reporting group description

Subject analysis set title

aH5N1, ≥18 years of age

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the exposed set who were in the solicited safety set and/or in the unsolicited safety set who received aH5N1.

Subject analysis set title

aTIV, ≥18 years of age

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in the exposed set who were in the solicited safety set and/or in the unsolicited safety set who received aH5N1.

Primary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 43/Day 1), as determined by HI assay

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End point title

Immunogenicity Endpoint: Geometric Mean Ratios (Day 43/Day 1), as determined by HI assay ^[1]

End point description

Geometric Mean ratios (GMRs) on Day 43 versus Day 1 (baseline) in adult (18 through 60 years of age) and elderly (≥61 years of age) 3 weeks after the second vaccination (Day 43) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. Full Analysis Set (FAS) for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Primary

End point timeframe

Day 43: Day 1

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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[2]	31 ^[3]	58 ^[4]	33 ^[5]	147 ^[6]	31 ^[7]	62	26
Units: titer ratios
geometric mean (confidence interval 95%)	2.01 (1.69 to 2.39)	1.09 (0.75 to 1.59)	3.61 (2.67 to 4.89)	1.09 (0.73 to 1.63)	2.40 (1.98 to 2.92)	1.37 (0.90 to 2.08)	2.94 (2.16 to 4.01)	1.05 (0.65 to 1.71)

Notes
[2] - N for Day 43 = 143
[3] - N for Day 43 = 30
[4] - N for Day 43 = 57
[5] - N for Day 43 = 32
[6] - N for Day 43 = 139
[7] - N for Day 43 = 30

No statistical analyses for this end point

Primary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion on Day 43 as determined by HI assay

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End point title

Immunogenicity Endpoint: Percentage of subjects achieving seroconversion on Day 43 as determined by HI assay ^[8]

End point description

Percentage of subjects achieving seroconversion (defined as HI ≥1:40 for subjects who were seronegative at baseline [Day 1 HI titer <1:10] or a minimum 4-fold increase in HI titer for subjects who were seropositive at baseline [Day 1 HI titer ≥1:10]) on Day 43 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. Full Analysis Set (FAS) for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Primary

End point timeframe

Day 43

Notes
[8] - 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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[9]	31 ^[10]	58 ^[11]	33 ^[12]	147 ^[13]	31 ^[14]	62	26
Units: percentage of subjects
number (confidence interval 95%)	19.18 (13.1 to 26.5)	0 (0 to 0)	43.10 (30.2 to 56.8)	3.03 (0.08 to 15.8)	24.49 (17.8 to 32.3)	3.23 (0.08 to 16.7)	30.65 (19.6 to 43.7)	3.85 (0.1 to 19.6)

Notes
[9] - N for Day 43 = 143
[10] - N for Day 43 = 30
[11] - N for Day 43 = 57
[12] - N for Day 43 = 32
[13] - N for Day 43 = 139
[14] - N for Day 43 = 30

No statistical analyses for this end point

Primary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 (Day 43)

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End point title

Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 (Day 43) ^[15]

End point description

Percentage of subjects with HI titer ≥1:40 on Day 43 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. Full Analysis Set (FAS) for primary objective: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Primary

End point timeframe

Day 43

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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[16]	31 ^[17]	58 ^[18]	33 ^[19]	147 ^[20]	31 ^[21]	62	26
Units: percentage of subjects
number (confidence interval 95%)	20 (14 to 27.8)	0 (0 to 0)	46 (32.4 to 59.3)	3 (0.08 to 16.2)	27 (20.1 to 35.5)	7 (0.8 to 22.1)	32 (20.9 to 45.3)	4 (0.1 to 19.6)

Notes
[16] - N for Day 43 = 143
[17] - N for Day 43 = 30
[18] - N for Day 43 = 57
[19] - N for Day 43 = 32
[20] - N for Day 43 = 139
[21] - N for Day 43 = 30

No statistical analyses for this end point

Primary: Safety Endpoint: Percentage of subjects with solicited local, solicited systemic, and other AEs

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End point title

Safety Endpoint: Percentage of subjects with solicited local, solicited systemic, and other AEs ^[22]

End point description

Percentage of subjects with solicited AEs that occur within 7 days following each vaccination Solicited Safety Set: All subjects in the Exposed Set with any solicited AE data and/or indicators of solicited AEs (ie, use of analgesics/antipyretics).

End point type

Primary

End point timeframe

Day 1 through Day 7

Notes
[22] - 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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥18 years of age	aTIV, ≥18 years of age
Number of subjects analysed	415	122
Units: percentage of subjects
number (not applicable)
Solicited AEs, Any	75.9	73.8
Solicited Local AEs	68.7	68.0
Solicited Systemic AEs	53.5	53.3
Other	5.8	6.6

No statistical analyses for this end point

Primary: Safety Endpoint: Percentage of subjects with unsolicited AEs reported

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End point title

Safety Endpoint: Percentage of subjects with unsolicited AEs reported ^[23]

End point description

Percentage of subjects with any unsolicited AEs reported within 21 days after each vaccination within each vaccine group. Unsolicited Safety Set: All subjects in the Exposed Set with unsolicited AE data.

End point type

Primary

End point timeframe

Day 1 through Day 21

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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥18 years of age	aTIV, ≥18 years of age
Number of subjects analysed	413	122
Units: Percentage of subjects
number (not applicable)
Unsolicited AEs, Any	42.4	33.6
Unsolicited AEs, Mild	17.7	11.5
Unsolicited AEs, Moderate	19.4	17.2
Unsolicited AEs, Severe	5.3	4.9
Unsolicited AEs, Related	10.4	7.4

No statistical analyses for this end point

Primary: Safety Endpoint: Percentage of subjects with SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to withdrawal from the study

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End point title

Safety Endpoint: Percentage of subjects with SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to withdrawal from the study ^[24]

End point description

Percentage of subjects reporting SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to withdrawal from the study as collected from Day 1 through Day 202. Unsolicited Safety Set: All subjects in the Exposed Set with unsolicited AE data.

End point type

Primary

End point timeframe

Day 1 through Day 202

Notes
[24] - 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: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥18 years of age	aTIV, ≥18 years of age
Number of subjects analysed	415 ^[25]	122
Units: Percentage of subjects
number (not applicable)
Serious Adverse Events (SAE)	3.4	4.1
Related SAEs	0.2	0
Medically attended AEs	37.4	28.7
AESIs	0	0
NOCDs	3.1	0.8
AEs leading to withdrawal	1.0	0
AEs leading to death	0.5	0

Notes
[25] - N for SAEs, related SAEs, AEs leading to withdrawal and AEs leading to death = 413

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios: Day 22/Day 1 and Day 43/Day 1 as determined by SRH

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End point title

Immunogenicity Endpoint: Geometric Mean Ratios: Day 22/Day 1 and Day 43/Day 1 as determined by SRH

End point description

Geometric Mean ratios (GMRs) for Day 22/Day 1 and Day 43/Day 1 as determined by single radial hemolysis (SRH) in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions. FAS for Secondary Objective. SRH - All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (SRH assay) at baseline (Day 1), 3 weeks after the first vaccination (Day 22) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Secondary

End point timeframe

Day 22/Day 1 and Day 43/Day 1

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[26]	31 ^[27]	58 ^[28]	33 ^[29]	147 ^[30]	31 ^[31]	62	26
Units: titer ratios
geometric mean (confidence interval 95%)
Day 22/Day 1 - SRH	1.65 (1.43 to 1.90)	1.44 (1.05 to 1.97)	2.71 (2.19 to 3.36)	1.27 (0.95 to 1.69)	1.76 (1.52 to 2.03)	1.41 (1.03 to 1.93)	1.69 (1.38 to 2.06)	1.29 (0.95 to 1.77)
Day 43/Day 1 - SRH	3.16 (2.69 to 3.73)	1.86 (1.30 to 2.66)	7.10 (5.85 to 8.62)	1.49 (1.15 to 1.93)	3.15 (2.70 to 3.68)	1.49 (1.07 to 2.08)	2.83 (2.24 to 3.58)	1.24 (0.86 to 1.79)

Notes
[26] - N for Day 22 = 144 N for Day 43 = 143
[27] - N for Day 22 = 30 N for Day 43 = 30
[28] - N for Day 43 = 57
[29] - N for Day 22 = 32 N for Day 43 = 32
[30] - N for Day 22 = 142 N for Day 43 = 139
[31] - N for Day 22 = 30 N for Day 43 = 30

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subject achieving seroconversion on Day 22 and Day 43 as determined by SRH assay

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End point title

Immunogenicity Endpoint: Percentage of subject achieving seroconversion on Day 22 and Day 43 as determined by SRH assay

End point description

Percentage of subjects achieving seroconversion on Day 22 and Day 43 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by single radial hemolysis (SRH) assay. FAS for Secondary Objective. SRH - All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (SRH assay) at baseline (Day 1), 3 weeks after the first vaccination (Day 22) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Secondary

End point timeframe

Day 22 and Day 43

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[32]	31 ^[33]	58 ^[34]	33 ^[35]	147 ^[36]	31 ^[37]	62	23
Units: percentage of subjects
number (confidence interval 95%)
Day 22 - SRH	33.33 (25.7 to 41.7)	30.00 (14.7 to 49.4)	63.79 (50.1 to 76)	25.00 (11.5 to 43.4)	38.03 (30 to 46.5)	26.67 (12.3 to 45.9)	35.48 (23.7 to 48.7)	19.23 (6.6 to 39.4)
Day 43 - SRH	61.54 (53 to 69.5)	50.00 (31.3 to 68.7)	89.47 (78.5 to 96)	37.50 (21.1 to 56.3)	64.75 (56.2 to 72.7)	20.00 (7.7 to 38.6)	56.45 (43.3 to 69)	19.23 (6.6 to 39.4)

Notes
[32] - N for Day 22 = 144 N for Day 43 = 143
[33] - N for Day 22 = 30 N for Day 43 = 30
[34] - N for Day 43 = 57
[35] - N for Day 22 = 32 N for Day 43 = 32
[36] - N for Day 22 = 142 N for Day 43 = 139
[37] - N for Day 22 = 30 N for Day 43 = 30

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subjects with SRH area ≥25mm2 on Day 1, Day 22 and Day 43

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End point title

Immunogenicity Endpoint: Percentage of subjects with SRH area ≥25mm2 on Day 1, Day 22 and Day 43

End point description

Percentage of subjects with with SRH area ≥25mm2 on Day 1, Day 22 and Day 43 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by single radial hemolysis (SRH) assay. FAS for Secondary Objective. SRH - All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (SRH assay) at baseline (Day 1), 3 weeks after the first vaccination (Day 22) and 3 weeks after the (planned) second vaccination (Day 43).

End point type

Secondary

End point timeframe

Day 1, Day 22 and Day 43

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[38]	31 ^[39]	58 ^[40]	33 ^[41]	147 ^[42]	31 ^[43]	62	26
Units: percentage of subjects
number (confidence interval 95%)
Day 1 - SRH	13.70 (8.6 to 20.4)	6.45 (0.8 to 21.4)	5.17 (1.1 to 14.4)	3.03 (0.08 to 15.8)	12.93 (8 to 19.4)	12.90 (3.6 to 29.8)	14.52 (6.9 to 25.8)	11.54 (2.4 to 30.2)
Day 22 - SRH	29.86 (22.5 to 38)	23.33 (9.9 to 42.3)	34.48 (22.5 to 48.1)	12.50 (3.5 to 29)	33.80 (26.1 to 42.2)	33.33 (17.3 to 52.8)	32.26 (20.9 to 45.3)	30.77 (14.3 to 51.8)
Day 43 - SRH	60.84 (52.3 to 68.9)	30.00 (14.7 to 49.4)	87.72 (76.3 to 94.9)	21.88 (9.3 to 40)	58.99 (50.3 to 67.3)	33.33 (17.3 to 52.8)	53.23 (40.1 to 66)	26.92 (11.6 to 47.8)

Notes
[38] - N for Day 22 = 144 N for Day 43 = 143
[39] - N for Day 22 = 30 N for Day 43 = 30
[40] - N for Day 43 = 57
[41] - N for Day 22 = 32 N for Day 43 = 32
[42] - N for Day 22 = 142 N for Day 43 = 139
[43] - N for Day 22 = 30 N for Day 43 = 30

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 22/Day 1) as determined by HI assay

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End point title

Immunogenicity Endpoint: Geometric Mean Ratios (Day 22/Day 1) as determined by HI assay

End point description

Geometric Mean ratios (GMRs) on Day 22 versus Day 1 (baseline) in adult (18 through 60 years of age) and elderly (≥61 years of age) 3 weeks after the first vaccination (Day 22) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. FAS for Secondary Objective, HI: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the first vaccination (Day 22).

End point type

Secondary

End point timeframe

Day 22/Day 1

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[44]	31 ^[45]	58	33 ^[46]	147 ^[47]	31	62	26
Units: titer ratios
geometric mean (confidence interval 95%)	1.29 (1.14 to 1.46)	1.17 (0.89 to 1.53)	1.62 (1.30 to 2.04)	1.08 (0.79 to 1.46)	1.47 (1.28 to 1.68)	1.03 (0.78 to 1.38)	1.73 (1.32 to 2.26)	1.14 (0.75 to 1.73)

Notes
[44] - N for Day 22 = 144
[45] - N for Day 22 = 30
[46] - N for Day 22 = 32
[47] - N for Day 22 = 142

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion (Day 22) as determined by HI assay

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End point title

Immunogenicity Endpoint: Percentage of subjects achieving seroconversion (Day 22) as determined by HI assay

End point description

Percentage of subjects achieving seroconversion (defined as HI ≥1:40 for subjects who were seronegative at baseline [Day 1 HI titer <1:10] or a minimum 4-fold increase in HI titer for subjects who were seropositive at baseline [Day 1 HI titer ≥1:10]) on Day 22 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. FAS for Secondary Objective, HI: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the first vaccination (Day 22).

End point type

Secondary

End point timeframe

Day 22

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[48]	31 ^[49]	58	33 ^[50]	147 ^[51]	31	62	26
Units: percentage of subjects
number (confidence interval 95%)	4.86 (2 to 9.8)	3.33 (0.08 to 17.2)	12.07 (5 to 23.3)	3.13 (0.08 to 16.2)	10.56 (6 to 16.8)	0 (0 to 0)	12.90 (5.7 to 23.9)	3.85 (0.1 to 19.6)

Notes
[48] - N for Day 22 = 144
[49] - N for Day 22 = 30
[50] - N for Day 22 = 32
[51] - N for Day 22 = 142

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 on Day 1 and Day 22 as determined by HI assay

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End point title

Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 on Day 1 and Day 22 as determined by HI assay

End point description

Percentage of subjects with HI titer ≥1:40 on Day 22 in adult (18 through 60 years of age) and elderly (≥61 years of age) according to CHMP immunogenicity criteria in subjects who are healthy or with immunosuppressive conditions as determined by Hemagglutination Inhibition (HI) assay. FAS for Secondary Objective, HI: All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data (HI assay) at baseline (Day 1) and 3 weeks after the first vaccination (Day 22).

End point type

Secondary

End point timeframe

Day 1 and Day 22

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[52]	31 ^[53]	58	33 ^[54]	147 ^[55]	31	62	26
Units: percentage of subjects
number (confidence interval 95%)
Day 1 - HI	1 (0.02 to 3.8)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	1 (0.02 to 3.7)	0 (0 to 0)	2 (0.04 to 8.7)	0 (0 to 0)
Day 22 - HI	6 (2.4 to 10.7)	3 (0.08 to 17.2)	12 (5 to 23.3)	3 (0.08 to 16.2)	11 (6 to 16.8)	0 (0 to 0)	15 (6.9 to 25.8)	4 (0.1 to 19.6)

Notes
[52] - N for Day 22 = 144
[53] - N for Day 22 = 30
[54] - N for Day 22 = 32
[55] - N for Day 22 =142

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Geometric Mean Titers (HI) and Geometric Mean Area (SRH) at Day 1, Day 22 and Day 43 as determined by HI and SRH

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End point title

Immunogenicity Endpoint: Geometric Mean Titers (HI) and Geometric Mean Area (SRH) at Day 1, Day 22 and Day 43 as determined by HI and SRH

End point description

Geometric mean titers (HI) and Geomertric Mean Area (SRH) at the following time points: Day 1, Day 22 (3 weeks after the first vaccination), Day 43 (3 weeks after the second vaccination) in adult (18 through 60 years of age) and elderly (≥61 years of age) subjects. FAS for Secondary Objective. SRH and HI- All subjects in the All Enrolled Set who were randomized, received at least one study vaccination and provided immunogenicity data at baseline (Day 1, SRH and HI assay), 3 weeks after the first vaccination (Day 22, SRH and HI assay) and 3 weeks after the (planned) second vaccination (Day 43, SRH assay).

End point type

Secondary

End point timeframe

Day 1, Day 22, Day 43

End point values	aH5N1, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aTIV, ≥ 18 to ≤ 60 years/with immunosuppressive conditions	aH5N1, ≥ 18 to ≤ 60 years, healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with immunosuppressive conditions	aTIV, ≥61 years/with immunosuppressive conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	146 ^[56]	31 ^[57]	58 ^[58]	33 ^[59]	147 ^[60]	31 ^[61]	62	26
Units: titer ratios
geometric mean (confidence interval 95%)
Day 1 - HI	5.14 (4.96 to 5.34)	5.00 (4.62 to 5.41)	5.09 (4.95 to 5.24)	5.00 (4.81 to 5.19)	5.37 (5.08 to 5.67)	5.29 (4.69 to 5.97)	5.44 (5.00 to 5.91)	5.00 (4.40 to 5.68)
Day 1 - SRH	8.54 (7.51 to 9.71)	8.20 (6.21 to 10.83)	7.11 (6.14 to 8.24)	6.28 (5.17 to 7.63)	8.34 (7.34 to 9.48)	10.04 (7.61 to 13.27)	8.25 (6.78 to 10.03)	8.93 (6.60 to 12.09)
Day 22 - HI	6.61 (5.83 to 7.48)	5.98 (4.55 to 7.86)	8.21 (6.55 to 10.30)	5.45 (4.02 to 7.39)	7.79 (6.81 to 8.90)	5.49 (4.12 to 7.32)	9.18 (7.02 to 12.01)	6.05 (3.99 to 9.17)
Day 22 - SRH	13.65 (11.84 to 15.74)	11.90 (8.71 to 16.26)	18.51 (14.95 to 22.92)	8.64 (6.47 to 11.52)	14.99 (12.99 to 17.30)	12.03 (8.79 to 16.46)	14.23 (11.62 to 17.42)	10.91 (7.98 to 14.91)
Day 43 - HI	10.31 (8.68 to 12.25)	5.57 (3.82 to 8.12)	18.28 (13.50 to 24.73)	5.50 (3.67 to 8.24)	12.76 (10.50 to 15.50)	7.26 (4.78 to 11.04)	15.60 (11.44 to 21.29)	5.59 (3.46 to 9.05)
Day 43 - SRH	26.50 (22.49 to 31.22)	15.58 (10.89 to 22.29)	48.58 (40.01 to 58.99)	10.17 (7.84 to 13.18)	26.85 (23.01 to 31.33)	12.71 (9.11 to 17.74)	23.91 (18.89 to 30.26)	10.48 (7.28 to 15.08)

Notes
[56] - N for Day 22 = 144 N for Day 43 = 143
[57] - N for Day 22 = 30 N for Day 43 = 30
[58] - N for Day 43 = 57
[59] - N for Day 22 = 32 N for Day 43 = 32
[60] - N for Day 22 = 142 N for Day 43 = 139
[61] - N for Day 43 = 30

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 through Day 202

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

aH5N1, ≥ 18 years, overall safety set

Reporting group description

All subjects in the exposed set who were in the solicited safety set and/or in the unsolicited safety set who received aH5N1.

Reporting group title

aTIV, ≥ 18 years, overall safety set

Reporting group description

All subjects in the exposed set who were in the solicited safety set and/or in the unsolicited safety set who received aTIV.

Serious adverse events	aH5N1, ≥ 18 years, overall safety set	aTIV, ≥ 18 years, overall safety set
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 415 (3.37%)	5 / 122 (4.10%)
number of deaths (all causes)	2	0
number of deaths resulting from adverse events	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastasis to liver
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal squamous cell carcinoma
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (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
Oedema peripheral
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Kidney transplant rejection
subjects affected / exposed	0 / 415 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Injury, poisoning and procedural complications
Laceration
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Road traffic accident
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (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
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 415 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (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
Renal disorder
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc annular tear
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (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
Erysipelas
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 415 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 415 (0.48%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Secondary syphilis
subjects affected / exposed	0 / 415 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 415 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 415 (0.24%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	aH5N1, ≥ 18 years, overall safety set	aTIV, ≥ 18 years, overall safety set
Total subjects affected by non serious adverse events
subjects affected / exposed	312 / 415 (75.18%)	90 / 122 (73.77%)
Nervous system disorders
Headache
subjects affected / exposed	91 / 415 (21.93%)	23 / 122 (18.85%)
occurrences all number	215	53
General disorders and administration site conditions
Chills
subjects affected / exposed	40 / 415 (9.64%)	10 / 122 (8.20%)
occurrences all number	93	22
Injection site erythema
subjects affected / exposed	82 / 415 (19.76%)	19 / 122 (15.57%)
occurrences all number	246	48
Injection site haemorrhage
subjects affected / exposed	22 / 415 (5.30%)	5 / 122 (4.10%)
occurrences all number	73	6
Injection site induration
subjects affected / exposed	74 / 415 (17.83%)	26 / 122 (21.31%)
occurrences all number	199	63
Injection site pain
subjects affected / exposed	249 / 415 (60.00%)	75 / 122 (61.48%)
occurrences all number	746	230
Fatigue
subjects affected / exposed	122 / 415 (29.40%)	37 / 122 (30.33%)
occurrences all number	447	138
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	52 / 415 (12.53%)	13 / 122 (10.66%)
occurrences all number	115	38
Nausea
subjects affected / exposed	44 / 415 (10.60%)	12 / 122 (9.84%)
occurrences all number	85	32
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	68 / 415 (16.39%)	22 / 122 (18.03%)
occurrences all number	204	53
Myalgia
subjects affected / exposed	145 / 415 (34.94%)	47 / 122 (38.52%)
occurrences all number	418	141
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	46 / 415 (11.08%)	12 / 122 (9.84%)
occurrences all number	118	30

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase III Stratified, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety, Tolerability, and Immunogenicity of Two Doses of aH5N1 when Administered to Adult and Elderly Subjects With and Without Immunosuppressive Conditions.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 43/Day 1), as determined by HI assay

Primary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 43/Day 1), as determined by HI assay

Primary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion on Day 43 as determined by HI assay

Primary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion on Day 43 as determined by HI assay

Primary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 (Day 43)

Primary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 (Day 43)

Primary: Safety Endpoint: Percentage of subjects with solicited local, solicited systemic, and other AEs

Primary: Safety Endpoint: Percentage of subjects with solicited local, solicited systemic, and other AEs

Primary: Safety Endpoint: Percentage of subjects with unsolicited AEs reported

Primary: Safety Endpoint: Percentage of subjects with unsolicited AEs reported

Primary: Safety Endpoint: Percentage of subjects with SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to withdrawal from the study

Primary: Safety Endpoint: Percentage of subjects with SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to withdrawal from the study

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios: Day 22/Day 1 and Day 43/Day 1 as determined by SRH

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios: Day 22/Day 1 and Day 43/Day 1 as determined by SRH

Secondary: Immunogenicity Endpoint: Percentage of subject achieving seroconversion on Day 22 and Day 43 as determined by SRH assay

Secondary: Immunogenicity Endpoint: Percentage of subject achieving seroconversion on Day 22 and Day 43 as determined by SRH assay

Secondary: Immunogenicity Endpoint: Percentage of subjects with SRH area ≥25mm2 on Day 1, Day 22 and Day 43

Secondary: Immunogenicity Endpoint: Percentage of subjects with SRH area ≥25mm2 on Day 1, Day 22 and Day 43

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 22/Day 1) as determined by HI assay

Secondary: Immunogenicity Endpoint: Geometric Mean Ratios (Day 22/Day 1) as determined by HI assay

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion (Day 22) as determined by HI assay

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving seroconversion (Day 22) as determined by HI assay

Secondary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 on Day 1 and Day 22 as determined by HI assay

Secondary: Immunogenicity Endpoint: Percentage of subjects with HI titer ≥1:40 on Day 1 and Day 22 as determined by HI assay

Secondary: Immunogenicity Endpoint: Geometric Mean Titers (HI) and Geometric Mean Area (SRH) at Day 1, Day 22 and Day 43 as determined by HI and SRH

Secondary: Immunogenicity Endpoint: Geometric Mean Titers (HI) and Geometric Mean Area (SRH) at Day 1, Day 22 and Day 43 as determined by HI and SRH

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III Stratified, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety, Tolerability, and Immunogenicity of Two Doses of aH5N1 when Administered to Adult and Elderly Subjects With and Without Immunosuppressive Conditions.