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Clinical Trial Results:
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 Underlying Medical Conditions.

Summary
EudraCT number	2011-003603-37
Trial protocol	DE
Global end of trial date	02 Apr 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_25

ISRCTN number

US NCT number

NCT02091908

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

23 Aug 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Apr 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 criteria1 in adult (18 through 60 years of age) and elderly (≥61 years of age) subjects who are healthy or with underlying medical condition, 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 underlying medical condition 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

10 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: 540

Worldwide total number of subjects

540

EEA total number of subjects

540

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)

348

From 65 to 84 years

191

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled from 6 study sites in Germany

Screening details

All enrolled subjects were included in the trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, 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 medical conditions

Arm description

Subjects ≥ 18 to ≤ 60 years of age with underlying medical 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, receive at least one study vaccination and provide 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 provide 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 medical conditions

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 in the deltoid muscle.

aH5N1, ≥ 18 to ≤ 60 years/healthy

Arm description

Healthy subjects ≥ 18 to ≤ 60 years of age who who provided immunogenicity data at Day 1 and Day 43 FAS for primary objective: All subjects in the All Enrolled Set who were randomized, receive at least one study vaccination and provide 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 provide 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

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, receive at least one study vaccination and provide 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 provide 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 in the deltoid muscle.

aH5N1, ≥61 years/with medical conditions

Arm description

Subjects ≥ 61 years of age with underlying medical 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, receive at least one study vaccination and provide 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 provide 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 medical conditions

Arm description

Subjects ≥ 61 years of age with underlying medical 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, receive at least one study vaccination and provide 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 provide 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 in 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, receive at least one study vaccination and provide 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 provide 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

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, receive at least one study vaccination and provide 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 provide 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 in the deltoid muscle.

Number of subjects in period 1	aH5N1, ≥ 18 to ≤ 60 years/with medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Started	146	34	59	31	149	31	58	32
Completed	138	34	57	31	142	31	58	32
Not completed	8	0	2	0	7	0	0	0
Adverse event, serious fatal	2	-	-	-	2	-	-	-
Consent withdrawn by subject	3	-	-	-	3	-	-	-
Adverse event, non-fatal	-	-	-	-	1	-	-	-
Lost to follow-up	3	-	2	-	1	-	-	-

Baseline characteristics

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Reporting group title

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

Reporting group description

Reporting group title

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

Reporting group description

Reporting group title

aTIV, ≥61 years/with medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy	Total
Number of subjects	146	34	59	31	149	31	58	32	540
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)	146	34	59	31	50	7	14	7	348
From 65-84 years	0	0	0	0	99	24	44	24	191
85 years and over	0	0	0	0	0	0	0	1	1
Age continuous
Units: years
arithmetic mean (standard deviation)	49.8 ± 9.37	46.9 ± 11.59	37.6 ± 11.81	41.1 ± 11.59	68.1 ± 5.53	69.9 ± 6.08	68.9 ± 5.28	69.3 ± 5.63	-
Gender categorical
Units: Subjects
Female	51	11	34	19	33	7	35	20	210
Male	95	23	25	12	116	24	23	12	330
Race
Units: Subjects
Black	0	0	1	0	0	0	0	0	1
White	146	34	58	31	149	31	58	32	539
Ethnicity
Units: Subjects
Hispanic or Latino	1	1	0	0	1	0	1	0	4
Not Hispanic or Latino	143	33	59	31	148	30	57	32	533
Not reported	1	0	0	0	0	0	0	0	1
Unknown	1	0	0	0	0	1	0	0	2
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	88.5 ± 22.20	88.4 ± 22.55	74.7 ± 14.63	77.7 ± 14.35	87.1 ± 17.41	85.1 ± 7.55	77.4 ± 13.66	76.1 ± 16.13	-
BMI
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	29.2 ± 6.82	28.5 ± 6.02	25.1 ± 3.94	26.4 ± 4.32	29.3 ± 5.59	28.7 ± 2.97	27.4 ± 3.58	26.8 ± 4.43	-

End points

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Reporting group title

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

Reporting group description

Reporting group title

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

Reporting group description

Reporting group title

aTIV, ≥61 years/with medical 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 aTIV.

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[2]	33	40 ^[3]	21	140 ^[4]	29 ^[5]	42 ^[6]	27
Units: titer ratios
geometric mean (confidence interval 95%)	2.42 (2.04 to 2.88)	1.13 (0.80 to 1.60)	3.44 (2.47 to 4.78)	1.09 (0.69 to 1.70)	2.64 (2.19 to 3.18)	1.19 (0.78 to 1.82)	2.44 (1.83 to 3.26)	1.30 (0.91 to 1.86)

Notes
[2] - N for Day 43 = 133
[3] - N for Day 43 = 39
[4] - N for Day 43 = 137
[5] - N for Day 43 = 27
[6] - N for Day 43 = 41

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 ^[7]

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 underlying medical 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
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Analyses for this endpoint were performed with descriptive statistics

End point values	aH5N1, ≥ 18 to ≤ 60 years/with medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136	33	40	21	140	29	42	27
Units: percentage of subjects
number (confidence interval 95%)	26.47 (19.3 to 34.7)	3.03 (0.08 to 15.8)	37.50 (22.7 to 54.2)	0 (0 to 0)	27.86 (20.6 to 36.1)	3.45 (0.09 to 17.8)	21.43 (10.3 to 36.8)	3.70 (0.09 to 19)

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) ^[8]

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[9]	33	40 ^[10]	21	140 ^[11]	29 ^[12]	42 ^[13]	27
Units: percentage of subjects
number (confidence interval 95%)	30 (22.4 to 38.6)	6 (0.7 to 20.2)	38 (23.4 to 55.4)	0 (0 to 0)	33 (25.1 to 41.4)	7 (0.9 to 24.3)	24 (12.4 to 40.3)	4 (0.09 to 19)

Notes
[9] - N for Day 43 = 133
[10] - N for Day 43 = 39
[11] - N for Day 43 = 137
[12] - N for Day 43 = 27
[13] - N for Day 43 = 41

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 ^[14]

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
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: 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	411	128
Units: percentage of subjects
number (not applicable)
Solicited AEs, Any	75.2	85.2
Solicited Local AEs	63.5	76.6
Solicited Systemic AEs	52.8	58.6
Other	7.3	6.3

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 ^[15]

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
[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 years of age	aTIV, ≥18 years of age
Number of subjects analysed	408	128
Units: percentage of subjects
number (not applicable)
Unsolicited AEs, Any	40.2	30.5
Unsolicited AEs, Mild	13.7	13.3
Unsolicited AEs, Moderate	17.2	10.9
Unsolicited AEs, Severe	9.3	6.3
Unsolicited AEs, Related	8.6	12.5

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 ^[16]

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
[16] - 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	411 ^[17]	128
Units: percentage of subjects
number (not applicable)
Serious Adverse Events (SAE)	11	2.3
Related SAEs	0	0
Medically attended AEs	32.8	25.0
AESIs	0	0
NOCDs	1.7	2.3
AEs leading to withdrawal	1.7	2.3
AEs leading to death	1.0	0

Notes
[17] - Ns for SAEs, related SAEs, AEs leading to withdrawal = 408

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) on 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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[18]	33 ^[19]	40 ^[20]	21	140 ^[21]	29 ^[22]	42 ^[23]	27
Units: titer ratios
geometric mean (confidence interval 95%)
Day 22/Day 1 - SRH	2.39 (2.09 to 2.73)	2.04 (1.55 to 2.67)	3.31 (2.55 to 4.30)	2.55 (1.79 to 3.63)	1.52 (1.37 to 1.69)	1.45 (1.15 to 1.84)	1.88 (1.48 to 2.38)	1.59 (1.19 to 2.13)
Day 43/ Day 1 - SRH	3.47 (3.05 to 3.94)	1.75 (1.36 to 2.27)	6.84 (5.47 to 8.56)	2.23 (1.64 to 3.03)	2.34 (2.08 to 2.64)	1.58 (1.20 to 2.07)	3.13 (2.44 to 4.01)	1.69 (1.24 to 2.29)

Notes
[18] - N for Day 22 = 130 N for Day 43 = 133
[19] - N for Day 22 = 32
[20] - N for Day 22 = 38 N for Day 43 = 39
[21] - N for Day 22 = 136 N for Day 43 = 137
[22] - N for Day 43 = 27
[23] - N for Day 22 = 41 N for Day 43 = 41

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[24]	33 ^[25]	40 ^[26]	21	140 ^[27]	29 ^[28]	42 ^[29]	27
Units: percentage of subjects
number (confidence interval 95%)
Day 22 - SRH	59.23 (50.3 to 67.8)	46.88 (29.1 to 65.3)	84.21 (68.7 to 94)	61.90 (38.4 to 81.9)	36.76 (28.7 to 45.5)	20.69 (8 to 39.7)	48.78 (32.9 to 64.9)	37.04 (19.4 to 57.6)
Day 43 - SRH	75.19 (67 to 82.3)	42.42 (25.5 to 60.8)	97.44 (86.5 to 99.94)	52.38 (29.8 to 74.3)	64.23 (55.6 to 72.2)	18.52 (6.3 to 38.1)	68.29 (51.9 to 81.9)	44.44 (25.5 to 64.7)

Notes
[24] - N for Day 22 = 130 N for Day 43 = 133
[25] - N for Day 22 = 32
[26] - N for Day 22 = 38 N for Day 43 = 39
[27] - N for Day 22 = 136 N for Day 43 = 137
[28] - N for Day 43 = 27
[29] - N for Day 22 = 41 N for Day 43 = 41

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[30]	33 ^[31]	40 ^[32]	21	140 ^[33]	29 ^[34]	42 ^[35]	27
Units: percentage of subjects
number (confidence interval 95%)
Day 1 - SRH	16.91 (11 to 24.3)	6.06 (0.7 to 20.2)	2.50 (0.06 to 13.2)	14.29 (3 to 36.3)	22.14 (15.6 to 29.9)	31.03 (15.3 to 50.8)	11.90 (4 to 25.6)	11.11 (2.4 to 29.2)
Day 22 - SRH	49.23 (40.4 to 58.1)	46.88 (29.1 to 65.3)	47.37 (31 to 64.2)	52.38 (29.8 to 74.3)	41.18 (32.8 to 49.6)	48.28 (29.4 to 67.5)	34.15 (20.1 to 50.6)	25.93 (11.1 to 46.3)
Day 43 - SRH	65.41 (56.7 to 73.4)	39.39 (22.9 to 57.9)	84.62 (69.5 to 94.1)	52.38 (29.8 to 74.3)	59.12 (50.4 to 67.4)	51.85 (31.9 to 71.3)	53.66 (37.4 to 69.3)	29.63 (13.8 to 50.2)

Notes
[30] - N for Day 22 = 130 N for Day 43 = 133
[31] - N for Day 22 = 32
[32] - N for Day 22 = 38 N for Day 43 = 39
[33] - N for Day 22 = 136 N for Day 43 = 137
[34] - N for Day 43 = 27
[35] - N for Day 22 and Day 43 = 41

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[36]	33 ^[37]	40 ^[38]	21	140 ^[39]	29	42 ^[40]	27
Units: titer ratios
geometric mean (confidence interval 95%)	1.57 (1.34 to 1.83)	1.07 (0.78 to 1.46)	1.95 (1.44 to 2.63)	1.18 (0.79 to 1.77)	1.59 (1.37 to 1.85)	1.24 (0.89 to 1.72)	1.66 (1.28 to 2.16)	1.12 (0.81 to 1.55)

Notes
[36] - N for Day 22 = 130
[37] - N for Day 22 = 32
[38] - N for Day 22 = 38
[39] - N for Day 22 = 136
[40] - N for Day 22 = 41

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[41]	33 ^[42]	40 ^[43]	21	140 ^[44]	29	42 ^[45]	27
Units: percentage of subjects
number (confidence interval 95%)	13.85 (8.4 to 21)	3.13 (0.08 to 16.2)	21.05 (9.6 to 37.3)	4.76 (0.12 to 23.8)	13.24 (8.0 to 20.1)	3.45 (0.09 to 17.8)	9.76 (2.7 to 23.1)	3.70 (0.09 to 19.0)

Notes
[41] - N for Day 22 = 130
[42] - N for Day 22 = 32
[43] - N for Day 22 = 38
[44] - N for Day 22 = 136
[45] - N for Day 22 = 41

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 underlying medical 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 medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[46]	33 ^[47]	40 ^[48]	21	140 ^[49]	29	42 ^[50]	27
Units: percentage of subjects
number (confidence interval 95%)
Day 1 - HI	2 (0.46 to 6.3)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	2 (0.44 to 6.1)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)
Day 22 - HI	15 (9.7 to 22.8)	3 (0.08 to 16.2)	21 (9.6 to 37.3)	5 (0.12 to 23.8)	15 (9.8 to 22.6)	7 (0.8 to 22.8)	12 (4.1 to 26.2)	4 (0.09 to 19)

Notes
[46] - N for Day 22 = 130
[47] - N for Day 22 = 32
[48] - N for Day 22 = 38
[49] - N for Day 22 = 136
[50] - N for Day 22 = 41

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 Geometric 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 and Day 43

End point values	aH5N1, ≥ 18 to ≤ 60 years/with medical conditions	aTIV, ≥ 18 to ≤ 60 years/with medical conditions	aH5N1, ≥ 18 to ≤ 60 years/healthy	aTIV, ≥ 18 to ≤ 60 years/healthy	aH5N1, ≥61 years/with medical conditions	aTIV, ≥61 years/with medical conditions	aH5N1, ≥61 years/healthy	aTIV, ≥61 years/healthy
Number of subjects analysed	136 ^[51]	33 ^[52]	40 ^[53]	21	140 ^[54]	29 ^[55]	42 ^[56]	27
Units: titer ratios
geometric mean (confidence interval 95%)
Day 1 - HI	5.47 (5.12 to 5.84)	5.27 (4.61 to 6.02)	5.00 (5.00 to 5.00)	5.00 (5.00 to 5.00)	5.80 (5.36 to 6.28)	6.20 (5.21 to 7.38)	5.21 (4.86 to 5.58)	5.13 (4.71 to 5.59)
Day 1 - SRH	9.42 (8.29 to 10.70)	7.55 (5.83 to 9.79)	7.01 (5.74 to 8.56)	9.26 (7.03 to 12.19)	11.92 (10.40 to 13.67)	15.70 (11.63 to 21.20)	9.10 (7.38 to 11.22)	8.88 (6.84 to 11.52)
Day 22 - HI	8.43 (7.22 to 9.85)	5.75 (4.20 to 7.87)	9.73 (7.19 to 13.16)	5.90 (3.93 to 8.86)	9.31 (8.01 to 10.83)	7.23 (5.21 to 10.03)	8.61 (6.63 to 11.19)	5.81 (4.21 to 8.03)
Day 22 - SRH	21.93 (19.18 to 25.06)	18.69 (14.26 to 24.50)	25.25 (19.45 to 32.77)	19.40 (13.62 to 27.63)	18.99 (17.04 to 21.15)	18.14 (14.34 to 22.95)	16.86 (13.31 to 21.36)	14.29 (10.68 to 19.13)
Day 43 - HI	13.17 (11.08 to 15.65)	6.13 (4.33 to 8.67)	17.20 (12.36 to 23.92)	5.43 (3.46 to 8.51)	15.42 (12.78 to 18.61)	6.96 (4.56 to 10.64)	12.66 (9.47 to 16.91)	6.73 (4.71 to 9.62)
Day 43 - SRH	31.53 (27.75 to 35.83)	15.94 (12.32 to 20.62)	51.76 (41.37 to 64.75)	16.87 (12.39 to 22.95)	29.62 (26.29 to 33.36)	19.98 (15.25 to 26.17)	27.97 (22.81 to 35.87)	15.08 (11.09 to 20.48)

Notes
[51] - N for Day 22 = 130 N for Day 43 = 133
[52] - N for Day 22 = 32
[53] - N for Day 22 = 38 N for Day 43 = 39
[54] - N for Day 22 = 136 N for Day 43 = 137
[55] - N for Day 43 = 27
[56] - N for Day 22 and Day 43 = 41

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

17.1

Reporting group title

aH5N1

Reporting group description

Reporting group title

aTIV

Reporting group description

Serious adverse events	aH5N1	aTIV
Total subjects affected by serious adverse events
subjects affected / exposed	45 / 411 (10.95%)	3 / 128 (2.34%)
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)
Lung neoplasm malignant
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasm
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Peripheral vascular disorder
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Knee arthroplasty
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Respiratory failure
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 411 (0.73%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 411 (0.00%)	1 / 128 (0.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Acute psychosis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adjustment disorder with depressed mood
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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
Bone contusion
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture displacement
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt thrombosis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord injury cervical
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular bypass dysfunction
subjects affected / exposed	2 / 411 (0.49%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 411 (0.73%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	2 / 411 (0.49%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Strabismus
subjects affected / exposed	0 / 411 (0.00%)	1 / 128 (0.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Colitis microscopic
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hidradenitis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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
Chronic kidney disease
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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 protrusion
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	0 / 411 (0.00%)	1 / 128 (0.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal disorder
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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
Chronic sinusitis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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	3 / 411 (0.73%)	1 / 128 (0.78%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Septic shock
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Liver abscess
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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
Diabetes mellitus
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	1 / 411 (0.24%)	0 / 128 (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	aTIV
Total subjects affected by non serious adverse events
subjects affected / exposed	306 / 411 (74.45%)	109 / 128 (85.16%)
Nervous system disorders
Headache
subjects affected / exposed	78 / 411 (18.98%)	30 / 128 (23.44%)
occurrences all number	214	72
General disorders and administration site conditions
Fatigue
subjects affected / exposed	131 / 411 (31.87%)	39 / 128 (30.47%)
occurrences all number	398	94
Injection site erythema
subjects affected / exposed	101 / 411 (24.57%)	37 / 128 (28.91%)
occurrences all number	233	102
Injection site haemorrhage
subjects affected / exposed	23 / 411 (5.60%)	14 / 128 (10.94%)
occurrences all number	93	38
Injection site induration
subjects affected / exposed	74 / 411 (18.00%)	41 / 128 (32.03%)
occurrences all number	227	114
Injection site pain
subjects affected / exposed	222 / 411 (54.01%)	82 / 128 (64.06%)
occurrences all number	650	257
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	49 / 411 (11.92%)	13 / 128 (10.16%)
occurrences all number	128	22
Nausea
subjects affected / exposed	26 / 411 (6.33%)	4 / 128 (3.13%)
occurrences all number	43	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	43 / 411 (10.46%)	19 / 128 (14.84%)
occurrences all number	154	46
Myalgia
subjects affected / exposed	124 / 411 (30.17%)	41 / 128 (32.03%)
occurrences all number	343	112
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	35 / 411 (8.52%)	9 / 128 (7.03%)
occurrences all number	99	23

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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: 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 Underlying Medical 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

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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 Underlying Medical Conditions.