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Clinical Trial Results:
LONG TERM IMMUNITY AND SAFETY WITH OR WITHOUT A BOOSTER DOSE FOLLOWING PRIMARY VACCINATION WITH THE JAPANESE ENCEPHALITIS VACCINE IC51 (IXIARO®) IN A PEDIATRIC POPULATION IN A JEV-ENDEMIC COUNTRY. OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY.

Summary
EudraCT number	2010-022265-10
Trial protocol	Outside EU/EEA
Global end of trial date	14 Oct 2013

Results information
Results version number	v1(current)
This version publication date	14 Apr 2016
First version publication date	14 Apr 2016
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

IC51-325

ISRCTN number

US NCT number

NCT01296360

WHO universal trial number (UTN)

Sponsor organisation name

Valneva Austria GmbH (formerly Intercell AG)

Sponsor organisation address

Campus Vienna Biocenter 3, Vienna, Austria, 1030

Public contact

Clinical Operations, Valneva Austria GmbH (formerly Intercell AG), 0043 1206200, info@valneva.com

Scientific contact

Clinical Operations, Valneva Austria GmbH (formerly Intercell AG), 0043 1206200, info@valneva.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000559-PIP01-09

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

26 Feb 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

Assessment of the immune response (geometric mean titers [GMTs] and seroconversion rates [SCRs]) 28 days after one single booster vaccination with the purified inactivated Japanese Encephalitis (JE) vaccine Ixiaro® administered at 12 months after primary immunization in a pediatric population from JEV endemic regions.

Protection of trial subjects

In the booster group, the subject’s legal representative or the subject, as applicable, was asked to report all symptoms (solicited and unsolicited AEs) after vaccination with IC51.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Dec 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Philippines: 300

Worldwide total number of subjects

300

EEA total number of subjects

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)

178

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited at 3 study centers in the Philippines. Recruitment started on 08-Dec-2010 and was completed on 29-Apr-2011. All subjects had participated in parent study IC51-323.

Screening details

Open-label, randomized, Phase 3 study in children aged ≥ 9 months to < 18 years.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Booster group

Arm description

Group received a booster dose of IC51 (Ixiaro®) at 12 months after the first vaccination with IC51 in study IC51-323 and was followed for another 24 months.

Arm type

Experimental

Investigational medicinal product name

IC51

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Subjects aged ≥ 14 months to < 3 years at Visit 2 received 1 vaccination of 0.25 ml IC51. Subjects aged ≥ 3 years to < 18 years at Visit 2 received 1 vaccination of 0.5 ml IC51.

Non-Booster group

Arm description

Group was followed for 36 months after the first vaccination with IC51 (Ixiaro®) in study IC51-323.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Booster group	Non-Booster group
Started	150	150
Completed	144	142
Not completed	6	8
Consent withdrawn by subject	1	-
Developed exclusion criteria	2	1
Non-compliance	2	4
Lost to follow-up	1	3

Baseline characteristics

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Reporting group title

Overall study

Reporting group description

Reporting group values	Overall study	Total
Number of subjects	300	300
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	62	62
Children (2-11 years)	178	178
Adolescents (12-17 years)	60	60
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (full range (min-max))	5.3 (1.2 to 17.3)	-
Gender categorical
Units: Subjects
Female	151	151
Male	149	149

End points

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Reporting group title

Booster group

Reporting group description

Group received a booster dose of IC51 (Ixiaro®) at 12 months after the first vaccination with IC51 in study IC51-323 and was followed for another 24 months.

Reporting group title

Non-Booster group

Reporting group description

Group was followed for 36 months after the first vaccination with IC51 (Ixiaro®) in study IC51-323.

Subject analysis set title

Booster 0.25 ml

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects aged ≥ 14 months to < 3 years at Visit 2 who had received 1 vaccination of 0.25 ml IC51.

Subject analysis set title

Booster 0.5 ml

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects aged ≥ 3 years to < 18 years at Visit 2 who had received 1 vaccination of 0.5 ml IC51.

Primary: SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose.

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End point title

SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose. ^[1] ^[2]

End point description

End point type

Primary

End point timeframe

1 Month after the IC51 booster dose.

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: No statistical analysis for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Non-Booster group did not receive treatment. Endpoint concerns Booster group only.

End point values	Booster group	Booster 0.25 ml	Booster 0.5 ml
Number of subjects analysed	148	81	67
Units: % of subjects
number (confidence interval 95%)	100 (97.5 to 100)	100 (95.5 to 100)	100 (94.6 to 100)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were recorded at all study visits until 36 months after the first IC51 vaccination in study IC51-323.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

13.0

Reporting group title

Booster group

Reporting group description

Group received a booster dose of IC51 (Ixiaro®) at 12 months after the first vaccination with IC51 in study IC51-323 and was followed for another 24 months.

Reporting group title

Non-Booster group

Reporting group description

Group was followed for 36 months after the first vaccination with IC51 (Ixiaro®) in study IC51-323.

Serious adverse events	Booster group	Non-Booster group
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 150 (4.67%)	3 / 150 (2.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Concussion
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 150 (0.00%)	1 / 150 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 150 (0.00%)	1 / 150 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax traumatic
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 150 (0.00%)	1 / 150 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Finger amputation
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (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
Paralysis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 150 (0.00%)	1 / 150 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Amoebic dysentery
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dengue fever
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 150 (0.67%)	0 / 150 (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	Booster group	Non-Booster group
Total subjects affected by non serious adverse events
subjects affected / exposed	99 / 150 (66.00%)	100 / 150 (66.67%)
General disorders and administration site conditions
Pyrexia
alternative assessment type: Non-systematic
subjects affected / exposed	10 / 150 (6.67%)	8 / 150 (5.33%)
occurrences all number	10	8
Fever
subjects affected / exposed	12 / 150 (8.00%)	0 / 150 (0.00%)
occurrences all number	12	0
Infections and infestations
Upper respiratory tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	37 / 150 (24.67%)	34 / 150 (22.67%)
occurrences all number	53	43
Rhinitis
alternative assessment type: Non-systematic
subjects affected / exposed	17 / 150 (11.33%)	16 / 150 (10.67%)
occurrences all number	20	17
Nasopharyngitis
subjects affected / exposed	16 / 150 (10.67%)	15 / 150 (10.00%)
occurrences all number	22	17
Varicella
alternative assessment type: Non-systematic
subjects affected / exposed	9 / 150 (6.00%)	14 / 150 (9.33%)
occurrences all number	9	14
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	7 / 150 (4.67%)	8 / 150 (5.33%)
occurrences all number	7	9
Bronchitis
alternative assessment type: Non-systematic
subjects affected / exposed	6 / 150 (4.00%)	8 / 150 (5.33%)
occurrences all number	7	11
Impetigo
alternative assessment type: Non-systematic
subjects affected / exposed	10 / 150 (6.67%)	4 / 150 (2.67%)
occurrences all number	10	4
Viral infection
subjects affected / exposed	9 / 150 (6.00%)	5 / 150 (3.33%)
occurrences all number	11	5

More information

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Were there any global substantial amendments to the protocol? Yes

30 May 2013

1) A change in provision of subsequent therapy (free vaccination after study end) has been made: Subjects randomized into the Non-booster group were supposed to receive another locally available vaccine against JEV after study end. Instead, another licensed pediatric vaccine (Measles, Mumps, Rubella vaccine) will now be offered at no cost to all study participants, according to approved prescribing information. 2) An update on the description of the method regarding JE neutralization tests for assessment of immunogenicity is given and a change in the Department name of Valneva´s laboratory is reflected. 3) The actual study start was reflected. The planned implementation date for the amended protocol (final version 2.0, Q2 2013) has been added. 4) Administrative changes have been made regarding change of Valneva study responsible personnel and revision of responsible Monitoring office. 5) A typographical error in the protocol title on the signature page has been corrected.

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:
LONG TERM IMMUNITY AND SAFETY WITH OR WITHOUT A BOOSTER DOSE FOLLOWING PRIMARY VACCINATION WITH THE JAPANESE ENCEPHALITIS VACCINE IC51 (IXIARO®) IN A PEDIATRIC POPULATION IN A JEV-ENDEMIC COUNTRY. OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose.

Primary: SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: LONG TERM IMMUNITY AND SAFETY WITH OR WITHOUT A BOOSTER DOSE FOLLOWING PRIMARY VACCINATION WITH THE JAPANESE ENCEPHALITIS VACCINE IC51 (IXIARO®) IN A PEDIATRIC POPULATION IN A JEV-ENDEMIC COUNTRY. OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose.

Primary: SCRs as defined by percentage of subjects with plaque reduction neutralization test (PRNT50) titers of ≥1:10 at 1 month after the booster dose.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
LONG TERM IMMUNITY AND SAFETY WITH OR WITHOUT A BOOSTER DOSE FOLLOWING PRIMARY VACCINATION WITH THE JAPANESE ENCEPHALITIS VACCINE IC51 (IXIARO®) IN A PEDIATRIC POPULATION IN A JEV-ENDEMIC COUNTRY. OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY.