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Clinical Trial Results:
A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of MEDI3250 Compared to Placebo in Healthy Japanese Children age 7 years through 18 years

Summary
EudraCT number	2014-003400-70
Trial protocol	Outside EU/EEA
Global end of trial date	20 Oct 2015

Results information
Results version number	v1
This version publication date	20 Mar 2016
First version publication date	20 Mar 2016
Other versions	v2

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

D2560C00006

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca Clinical Study Information Center

Sponsor organisation address

Room Tatnall Bldg 1800 Concord Pike PO Box 15437, Wilmington, DE, United States, 19850-5437

Public contact

INformation Center, AstraZeneca Clinical Study Information Center, 1+ 877-240-9479, informationcenter@astrazeneca.com

Scientific contact

Raburn Mallony, MedImmune, 1+ 301-398-0000, ClinicalTrialEnquiries@Medimmune.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

20 Oct 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Oct 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess the efficacy (the incidence of laboratory-confirmed influenza infection caused by any community-acquired wild-type strains matched to the vaccine) of MEDI3250 compared to placebo. To assess the safety and tolerability of MEDI3250 compared to placebo.

Protection of trial subjects

The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. The applicable regulatory requirements in Japan are ‘Good Clinical Practice for Trials on Drugs (MHLW Ordinance No. 28, 27 March 1997, partially revised by MHLW Ordinance and their related notifications. The Master Informed Consent Form will explain that: • Study data will be stored in a computer database, maintaining confidentiality in accordance with national data legislation • Subject data will be maintaining confidentiality in accordance with national data legislation • For data verification purposes, authorised representatives of AstraZeneca, a regulatory authority, an IRB may require direct access to parts of the hospital or practice source records relevant to the study, including subjects’ medical history • All data computer processed by AstraZeneca will be identified by study code and enrolment code (E-code) The combined data from the trivalent live, attenuated influenza vaccine development program and postmarketing experience provide substantial evidence to confirm the acceptable safety, tolerability, and efficacy of T/LAIV in individuals 24 months of age and older.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Oct 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 1369

Worldwide total number of subjects

1369

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)

849

Adolescents (12-17 years)

486

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

To enrol Japanese children age 7 years to through 18 years.

Screening details

To meet all of the inclusion criteria and none of the exclusion criteria for this study.

Number of subjects started

1369

Number of subjects completed

1301

Reason: Number of subjects

last patients randomization: 68

Period 1 title

Up to end April 2015 (6 months) (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

Are arms mutually exclusive

Yes

MEDI3250

Arm description

Arm type

Experimental

Investigational medicinal product name

N/A

Investigational medicinal product code

MEDI3250

Other name

Pharmaceutical forms

Suspension and solution for spray

Routes of administration

Nasal use

Dosage and administration details

intranasal administration of 0.2 mL (0.1 mL per nostril)

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Suspension and solution for spray

Routes of administration

Nasal use

Dosage and administration details

intranasal administration of 0.2 mL (0.1 mL per nostril)

Number of subjects in period 1 ^[1]	MEDI3250	Placebo
Started	868	433
Completed	865	432
Not completed	3	1
Consent withdrawn by subject	-	1
exclusion criteria 17	3	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 1,369 Japanese subjects whom written informed consent was provided were enrolled. Of these, 1,301 subjects were randomized to either MEDI3250 or placebo and received the investigational product.

Baseline characteristics

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Reporting group title

MEDI3250

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	MEDI3250	Placebo	Total
Number of subjects	868	433	1301
Age Categorical
Units: Subjects
Children (2-11 years)	534	277	811
Adolescents (12-17 years)	314	145	459
Adults (18-64 years)	20	11	31
Age Continuous
Units: years
arithmetic mean (standard deviation)	11 ± 3	10.8 ± 2.8	-
Gender Categorical
Units: Subjects
Female	408	226	634
Male	460	207	667
Number of Doses of Study Vaccine Received
Units: Subjects
One	841	421	1262
Two	27	12	39
Prior Influenza Vaccination
Units: Subjects
Yes	788	386	1174
No	80	47	127

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT

Subject analysis set title

Safety analysis set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety analysis set

Subject analysis set title

PPS

Subject analysis set type

Per protocol

Subject analysis set description

PPS

Subject analysis sets values	ITT	Safety analysis set	PPS
Number of subjects	1301	1301	1279
Age Categorical
Units: Subjects
Children (2-11 years)	811	811	801
Adolescents (12-17 years)	459	459	449
Adults (18-64 years)	31	31	29
Age Continuous
Units: years
arithmetic mean (standard deviation)	10.9 ± 2.9	10.9 ± 2.9	10.9 ± 2.9
Gender Categorical
Units: Subjects
Female	634	634	622
Male	667	667	657
Number of Doses of Study Vaccine Received
Units: Subjects
One	1262	1262	1240
Two	39	39	39
Prior Influenza Vaccination
Units: Subjects
Yes	1174	1174	1153
No	127	127	126

End points

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Reporting group title

MEDI3250

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT

Subject analysis set title

Safety analysis set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety analysis set

Subject analysis set title

PPS

Subject analysis set type

Per protocol

Subject analysis set description

PPS

Primary: Influenza Attacked (Matched Strain)

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End point title

Influenza Attacked (Matched Strain)

End point description

End point type

Primary

End point timeframe

Until end of influenza surveillance period

End point values	MEDI3250	Placebo
Number of subjects analysed	849	430
Units: number	0	1

Vaccine efficacy for matched strain

Comparison groups

MEDI3250 v Placebo

Number of subjects included in analysis

1279

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Vaccine Efficacy

Point estimate

100

Confidence interval

level

95%

sides

2-sided

lower limit

-1875.3

upper limit

100

Secondary: Influenza Attacked (Any Strain)

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End point title

Influenza Attacked (Any Strain)

End point description

End point type

Secondary

End point timeframe

Until end of influenza surveillance period

End point values	MEDI3250	Placebo
Number of subjects analysed	849	430
Units: number	215	146

Vaccine efficacy for any strain

Comparison groups

MEDI3250 v Placebo

Number of subjects included in analysis

1279

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Vaccine Efficacy

Point estimate

25.6

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

39.8

Secondary: Influenza Attacked (Matched Strain, by Strain)

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End point title

Influenza Attacked (Matched Strain, by Strain)

End point description

End point type

Secondary

End point timeframe

Until end of influenza surveillance period

End point values	MEDI3250	Placebo
Number of subjects analysed	849	430
Units: number
Strain A/H1N1	0	0
Strain A/H3N2	0	0
Strain B/Yamagata	0	1
Strain B/Victoria	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were collected from Day 1 until the end of the influenza surveillance period. Serious adverse events were collected from informed consent until the end of the influenza surveillance period.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

MEDI3250

Reporting group description

Nasal spray administration of MEDI3250 0.2 mL (0.1 mL per nostril)

Reporting group title

Total

Reporting group description

Nasal spray administration of study drug 0.2 mL (0.1 mL per nostril)

Reporting group title

Placebo

Reporting group description

Nasal spray administration of Placebo 0.2 mL (0.1 mL per nostril)

Serious adverse events	MEDI3250	Total	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 868 (0.35%)	6 / 1301 (0.46%)	3 / 433 (0.69%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Nervous system disorders
Convulsion
subjects affected / exposed	1 / 868 (0.12%)	1 / 1301 (0.08%)	0 / 433 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 868 (0.00%)	1 / 1301 (0.08%)	1 / 433 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteochondrosis
subjects affected / exposed	0 / 868 (0.00%)	1 / 1301 (0.08%)	1 / 433 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 868 (0.12%)	1 / 1301 (0.08%)	0 / 433 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	1 / 868 (0.12%)	1 / 1301 (0.08%)	0 / 433 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 868 (0.00%)	1 / 1301 (0.08%)	1 / 433 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	MEDI3250	Total	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	133 / 868 (15.32%)	205 / 1301 (15.76%)	72 / 433 (16.63%)
Gastrointestinal disorders
diarrhoea
subjects affected / exposed	10 / 868 (1.15%)	15 / 1301 (1.15%)	5 / 433 (1.15%)
occurrences all number	10	15	5
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation
subjects affected / exposed	18 / 868 (2.07%)	26 / 1301 (2.00%)	8 / 433 (1.85%)
occurrences all number	18	26	8
rhinorrhoea
subjects affected / exposed	14 / 868 (1.61%)	23 / 1301 (1.77%)	9 / 433 (2.08%)
occurrences all number	14	23	9
cough
subjects affected / exposed	7 / 868 (0.81%)	12 / 1301 (0.92%)	5 / 433 (1.15%)
occurrences all number	7	12	5
phinitia allergic
subjects affected / exposed	9 / 868 (1.04%)	11 / 1301 (0.85%)	2 / 433 (0.46%)
occurrences all number	9	11	2
Infections and infestations
nasopharyngitis
subjects affected / exposed	70 / 868 (8.06%)	106 / 1301 (8.15%)	36 / 433 (8.31%)
occurrences all number	70	106	36
bronchitis
subjects affected / exposed	5 / 868 (0.58%)	12 / 1301 (0.92%)	7 / 433 (1.62%)
occurrences all number	5	12	7

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 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of MEDI3250 Compared to Placebo in Healthy Japanese Children age 7 years through 18 years

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Influenza Attacked (Matched Strain)

Primary: Influenza Attacked (Matched Strain)

Secondary: Influenza Attacked (Any Strain)

Secondary: Influenza Attacked (Any Strain)

Secondary: Influenza Attacked (Matched Strain, by Strain)

Secondary: Influenza Attacked (Matched Strain, by Strain)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of MEDI3250 Compared to Placebo in Healthy Japanese Children age 7 years through 18 years

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Influenza Attacked (Matched Strain)

Primary: Influenza Attacked (Matched Strain)

Secondary: Influenza Attacked (Any Strain)

Secondary: Influenza Attacked (Any Strain)

Secondary: Influenza Attacked (Matched Strain, by Strain)

Secondary: Influenza Attacked (Matched Strain, by Strain)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of MEDI3250 Compared to Placebo in Healthy Japanese Children age 7 years through 18 years