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Clinical Trial Results:
An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children with Severe Eosinophilic Asthma

Summary
EudraCT number	2019-004638-40
Trial protocol	Outside EU/EEA
Global end of trial date	12 Sep 2022

Results information
Results version number	v1(current)
This version publication date	28 Mar 2023
First version publication date	28 Mar 2023
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

D3250C00025

ISRCTN number

US NCT number

NCT04305405

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, 151 85

Public contact

Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com

Scientific contact

Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001214-PIP01-11

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

12 Sep 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Sep 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the pharmacokinetics (PK) of benralizumab administered subcutaneously (SC) in children from 6 to 11 years of age with severe eosinophilic asthma.

Protection of trial subjects

This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Nov 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 19

Country: Number of subjects enrolled

Japan: 11

Worldwide total number of subjects

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)

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

This Phase III, open-label, parallel group study was conducted in pediatric participants with severe eosinophilic asthma at 17 investigational sites.

Screening details

The study consisted of a screening period (up to 4 weeks), treatment period [2 parts; Part A (16 weeks) followed by Part B (32 weeks)], and a safety follow-up visit at Week 52. A total of 30 participants were enrolled in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Benralizumab Dose 1, Aged 6-14 Years

Arm description

All participants with body weight <35 kilograms (kg) at screening received benralizumab Dose 1 subcutaneous (SC) injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 1 at Weeks 24, 32, and 40 in Part B.

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

MEDI-563

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Benralizumab was administered as a sc injection in either upper arm, thighs, or the abdomen in rotation.

Benralizumab Dose 2, Aged 6-14 Years

Arm description

All participants with body weight >=35 kg or aged 12-14 years (irrespective of body weight) at screening received benralizumab Dose 2 SC injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 2 at Weeks 24, 32, and 40 in Part B.

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

MEDI-563

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Benralizumab was administered as a sc injection in either upper arm, thighs, or the abdomen in rotation.

Number of subjects in period 1	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years
Started	15	15
Completed	15	14
Not completed	0	1
Withdrawal by parent/guardian	-	1

Baseline characteristics

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Reporting group title

Benralizumab Dose 1, Aged 6-14 Years

Reporting group description

Reporting group title

Benralizumab Dose 2, Aged 6-14 Years

Reporting group description

Reporting group values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Total
Number of subjects	15	15	30
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	8.3 ± 2.02	9.8 ± 1.93	-
Sex: Female, Male
Units: participants
Female	4	7	11
Male	11	8	19
Race/Ethnicity, Customized
Units: Subjects
White	4	4	8
Black or African American	3	5	8
Asian	8	3	11
American Indian or Alaska Native	0	0	0
Native Hawaiian or other Pacific Islander	0	0	0
Other	0	3	3
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	1	5	6
Not Hispanic or Latino	14	10	24

End points

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Reporting group title

Benralizumab Dose 1, Aged 6-14 Years

Reporting group description

Reporting group title

Benralizumab Dose 2, Aged 6-14 Years

Reporting group description

Subject analysis set title

Benralizumab Dose 1, Aged 6-11 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with body weight <35 kg at screening received benralizumab Dose 1 SC injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 1 at Weeks 24, 32, and 40 in Part B.

Subject analysis set title

Benralizumab Dose 2, Aged 6-11 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with body weight >=35 kg at screening received benralizumab Dose 2 SC injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 2 at Weeks 24, 32, and 40 in Part B.

Subject analysis set title

Benralizumab Dose 1, Aged 6-11 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Benralizumab Dose 2, Aged 6-11 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

All participants

Subject analysis set type

Full analysis

Subject analysis set description

All participants aged 6-14 years enrolled in this study irrespective of study treatment received were included in this arm.

Primary: Clearance of Benralizumab

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End point title

Clearance of Benralizumab ^[1]

End point description

Blood samples were collected to determine the clearance of benralizumab. This was an empirical Bayesian estimate (EBE) derived posthoc using population PK analysis. The PK analysis set consisted of all participants who received at least 1 dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 1 post dose quantifiable serum PK observation.

End point type

Primary

End point timeframe

Pre-dose on Days 0, 28, 56, 112, 168 and post-dose on Days 1, 7, 14, 84, 336; and at early discontinuation or withdrawal visit

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 additional statistical analysis was pre-specified for this endpoint.

End point values	All participants
Number of subjects analysed	30
Units: liter (L) per day
arithmetic mean (standard deviation)	0.156 ± 0.0598

No statistical analyses for this end point

Primary: Area Under the Serum Concentration-Time Curve From Time Zero to Day 28 (AUC0-28) of Benralizumab

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End point title

Area Under the Serum Concentration-Time Curve From Time Zero to Day 28 (AUC0-28) of Benralizumab ^[2]

End point description

Blood samples were collected to determine the AUC0-28 of benralizumab and it was calculated by linear up/log down trapezoidal summation. The PK parameters were estimated using non-compartmental analysis method. The Non-compartmental analysis (NCA) set consisted of all participants who received the first dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 3 quantifiable serum PK observations post-dose on Days 1, 7, 14, and 28. Only those participants with data available were analyzed.

End point type

Primary

End point timeframe

Pre-dose on Days 0, 28 and post-dose on Days 1, 7, 14

Notes
[2] - 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 additional statistical analysis was pre-specified for this endpoint.

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	10	11	10	10
Units: nanogramday per milliliter (ngday/mL)
geometric mean (geometric coefficient of variation)	36918.01 ± 24.61	73670.51 ± 38.86	36918.01 ± 24.61	75593.37 ± 39.96

No statistical analyses for this end point

Primary: Maximum Observed Serum Concentration (Cmax) of Benralizumab

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End point title

Maximum Observed Serum Concentration (Cmax) of Benralizumab ^[3]

End point description

Blood samples were collected to determine Cmax of benralizumab and it was directly calculated from the individual concentration-time curve. The PK parameters were estimated using non-compartmental analysis method. The NCA set consisted of all participants who received the first dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 3 quantifiable serum PK observations post-dose on Days 1, 7, 14, and 28.

End point type

Primary

End point timeframe

Pre-dose on Days 0, 28, 56, 112, 168 and post-dose on Days 1, 7, 14, 84, 336; and at early discontinuation or withdrawal visit

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No additional statistical analysis was pre-specified for this endpoint.

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: ng/mL
geometric mean (geometric coefficient of variation)	1901.18 ± 28.42	3090.85 ± 43.66	1901.18 ± 28.42	3118.69 ± 47.35

No statistical analyses for this end point

Primary: Time to Achieve Maximum Observed Serum Concentration (tmax) of Benralizumab

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End point title

Time to Achieve Maximum Observed Serum Concentration (tmax) of Benralizumab ^[4]

End point description

Blood samples were collected to determine the tmax of benralizumab and it was directly calculated from the individual concentration-time curve. The PK parameters were estimated using non-compartmental analysis method. The NCA set consisted of all participants who received the first dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 3 quantifiable serum PK observations post-dose on Days 1, 7, 14, and 28.

End point type

Primary

End point timeframe

Pre-dose on Days 0, 28, 56, 112, 168 and post-dose on Days 1, 7, 14, 84, 336; and at early discontinuation or withdrawal visit

Notes
[4] - 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 additional statistical analysis was pre-specified for this endpoint.

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: day
median (full range (min-max))	6.91 (0.93 to 14.95)	7.94 (1.10 to 14.01)	6.91 (0.93 to 14.95)	7.26 (1.10 to 14.01)

No statistical analyses for this end point

Primary: Terminal Phase Elimination Half-Life (t1/2) of Benralizumab

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End point title

Terminal Phase Elimination Half-Life (t1/2) of Benralizumab ^[5]

End point description

Blood samples were collected to determine the t1/2 of benralizumab and it was calculated as natural logarithm of 2 [ln(2)]/terminal rate constant (λZ). This was an EBE derived posthoc using population PK analysis. The PK analysis set consisted of all participants who received at least 1 dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 1 post dose quantifiable serum PK observation.

End point type

Primary

End point timeframe

Pre-dose on Days 0, 28, 56, 112, 168 and post-dose on Days 1, 7, 14, 84, 336; and at early discontinuation or withdrawal visit

Notes
[5] - 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 additional statistical analysis was pre-specified for this endpoint.

End point values	All participants
Number of subjects analysed	30
Units: day
median (full range (min-max))	14.4 (6.94 to 23.4)

No statistical analyses for this end point

Primary: Trough Concentration of Benralizumab at Week 16 (Ctrough16)

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End point title

Trough Concentration of Benralizumab at Week 16 (Ctrough16) ^[6]

End point description

Blood samples were collected to determine the trough concentration at Week 16, the lowest concentration reached by benralizumab before the next dose was administered. The PK parameters were estimated using non-compartmental analysis method. The NCA set consisted of all participants who received the first dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 3 quantifiable serum PK observations post-dose on Days 1, 7, 14, and 28. Only those participants with data available were analyzed.

End point type

Primary

End point timeframe

Pre-dose on Day 112

Notes
[6] - 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 additional statistical analysis was pre-specified for this endpoint.

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	14	15	13
Units: ng/mL
geometric mean (geometric coefficient of variation)	142.42 ± 256.34	340.46 ± 363.69	142.42 ± 256.34	339.35 ± 409.24

No statistical analyses for this end point

Primary: Change From Baseline in Peripheral Blood Eosinophil Count up to Week 48

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End point title

Change From Baseline in Peripheral Blood Eosinophil Count up to Week 48 ^[7]

End point description

Blood samples were collected for determination of eosinophil count levels and were assessed in a central laboratory. Baseline is the last non-missing measurement prior to the first dose of study treatment. The Safety Analysis set consisted of all participants who received at least 1 dose of benralizumab. Only those participants with data available were analyzed. Here, n= number of participants analyzed at specific timepoint.

End point type

Primary

End point timeframe

Baseline (Day 0) and at Weeks 4, 8, 12, 16, 24 and 48

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: No additional statistical analysis was pre-specified for this endpoint.

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: cells/microliters
arithmetic mean (standard deviation)
Week 4 (n=15, 15, 15, 13)	-447.3 ± 283.76	-455.3 ± 385.58	-447.3 ± 283.76	-436.9 ± 408.28
Week 8 (n=15, 15, 15, 13)	-445.3 ± 276.20	-470.7 ± 374.25	-445.3 ± 276.20	-453.8 ± 396.03
Week 12 (n=15, 14, 15, 12)	-443.3 ± 286.85	-472.9 ± 393.49	-443.3 ± 286.85	-455.8 ± 419.32
Week 16 (n=15, 12, 15, 11)	-446.7 ± 279.12	-430.0 ± 378.68	-446.7 ± 279.12	-402.7 ± 384.61
Week 24 (n=12, 14, 12, 13)	-354.2 ± 323.99	-457.9 ± 397.77	-354.2 ± 323.99	-436.9 ± 405.90
Week 48 (n=15, 14, 15, 13)	-434.0 ± 286.15	-474.3 ± 385.04	-434.0 ± 286.15	-453.8 ± 392.78

No statistical analyses for this end point

Secondary: Body Weight-Adjusted Clearance of Benralizumab

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End point title

Body Weight-Adjusted Clearance of Benralizumab

End point description

Blood samples were collected to determine the clearance of benralizumab. This was an EBE derived posthoc using population PK analysis. The PK analysis set consisted of all participants who received at least 1 dose of benralizumab for whom PK blood samples were not assumed to be affected by factors such as protocol violations and who had at least 1 post dose quantifiable serum PK observation.

End point type

Secondary

End point timeframe

Pre-dose on Days 0, 28, 56, 112, 168 and post-dose on Days 1, 7, 14, 84, 336; and at early discontinuation or withdrawal visit

End point values	All participants
Number of subjects analysed	30
Units: L/day/kilogram
arithmetic mean (standard deviation)	0.00408 ± 0.000764

No statistical analyses for this end point

Secondary: Number of Participants With Anti-Drug Antibodies (ADA) Response to Benralizumab

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End point title

Number of Participants With Anti-Drug Antibodies (ADA) Response to Benralizumab

End point description

ADA prevalence:ADA positive (+ve) at any time point including baseline and/or post baseline(PB). Treatment (Rx) induced ADA+ve:ADA negative (-ve) at baseline and PB ADA+ve. Rx-boosted ADA+ve:baseline +ve ADA titer boosted by >4-fold or higher following study drug administration. Rx-emergent ADA+ve:Rx-induced ADA+ve/treatment-boosted ADA+ve. Persistently +ve ADA:having at least 2 PB ADA+ve assessments with at least 16 weeks (112 days) between first and last +ve assessments/ADA+ve result at last available assessment. Transiently +ve ADA:having at least 1 PB ADA+ve assessment(s) & not persistently ADA+ve. Neutralizing antibodies (nAb) prevalence:nAb+ve at baseline and/or PB. nAb incidence: nAb-ve at baseline (or ADA-ve at baseline) and nAb+ve at any PB visit. The Safety Analysis set consisted of all participants who received at least 1 dose of benralizumab. Only those participants with data available were analyzed.n=number of participants analyzed for specified ADA category.

End point type

Secondary

End point timeframe

Pre-dose at Baseline (Day 0), Weeks 8, 16 and 24 and post-dose at Week 48; and at early discontinuation or withdrawal visit

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: participants
ADA prevalence (n=15, 15, 15, 13)	3	1	3	1
Treatment-emergent ADA+ve (n=15, 15, 15, 13)	3	1	3	1
Post-baseline (PB) ADA+ve (n=15, 15, 15, 13)	3	1	3	1
Baseline and at least 1 PB ADA+ve (n=13,15,13,13)	0	0	0	0
Only baseline ADA+ve (n=13, 15, 13, 13)	0	0	0	0
Persistently ADA+ve (n=15, 15, 15, 13)	1	0	1	0
Transiently ADA +ve (n=15, 15, 15, 13)	2	1	2	1
nAb prevalence (n=15, 15, 15, 13)	3	1	3	1
nAb incidence (n=15, 15, 15, 13)	3	1	3	1

No statistical analyses for this end point

Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) up to Week 48

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End point title

Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) up to Week 48

End point description

The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration and was measured by spirometry. Baseline is the last non-missing measurement with acceptable quality prior to the first dose of study treatment. The Safety Analysis set consisted of all participants who received at least 1 dose of benralizumab. Only those participants with data available were analyzed. Here, n= number of participants analyzed at specific timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 0) and at Weeks 16 and 48

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: liters
arithmetic mean (standard deviation)
Week 16 (n=11, 8, 11, 7)	-0.001 ± 0.2434	-0.165 ± 0.2609	-0.001 ± 0.2434	-0.119 ± 0.2435
Week 48 (n=15, 13, 15, 12)	0.003 ± 0.3412	0.428 ± 0.4209	0.003 ± 0.3412	0.425 ± 0.4395

No statistical analyses for this end point

Secondary: Change From Baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) Score up to Week 48

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End point title

Change From Baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) Score up to Week 48

End point description

The ACQ-IA was a 6-item assessment comprised of 6 patient-reported items. Participants were asked to record their experience with 5 symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and use of short-acting beta-2 agonist (SABA) over the previous week using a 7-point scale (0 = no impairment and 6 = maximum impairment). The ACQ-IA score was calculated by taking the mean of the 7 equally weighted items. The score ranged from 0 (well controlled) to 6 (extremely poorly controlled). Higher scores indicated poor asthma control. Baseline is the last non-missing measurement prior to the first dose of study treatment. The Safety Analysis set consisted of all participants who received at least 1 dose of benralizumab. Only those participants with data available were analyzed. Here, n= number of participants analyzed at specific timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 0), at Weeks 16 and 48; and at early discontinuation or withdrawal visit

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: scores on a scale
arithmetic mean (standard deviation)
Week 16 (n=15, 13, 15, 12)	-0.62 ± 0.890	-1.06 ± 1.696	-0.62 ± 0.890	-1.18 ± 1.717
Week 48 (n=14, 13, 14, 12)	-0.56 ± 1.252	-1.31 ± 1.324	-0.56 ± 1.252	-1.36 ± 1.369

No statistical analyses for this end point

Secondary: Number of Responders in Interviewer-Administered Patient Global Impression of Change (PGIC)-IA and Clinician Global Impression of Change (CGIC) Responder Status Questionnaires

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End point title

Number of Responders in Interviewer-Administered Patient Global Impression of Change (PGIC)-IA and Clinician Global Impression of Change (CGIC) Responder Status Questionnaires

End point description

The PGIC-IA and CGIC instruments were used for an overall evaluation of response to Rx, conducted separately by Investigator and by participant (administered by trained individuals to help the child understand the question and response options), using a 7-point scale:1=very much improved;2=much improved;3=minimally improved;4=no change;5=minimally worse;6=much worse;7=very much worse. The clinician and participant rated degree of change in overall asthma status compared to start of study Rx visit. Participants were defined as responders based on categorized responses for PGIC-IA and CGIC. Responder status categories included: Improved=Very much improved, Much improved, Minimally improved, Much improved=Much improved, Very much improved, Very much improved=Very much improved. CGIC=PGIC-IA indicates agreement between CGIC and PGIC-IA assessments of response to treatment at the same visit. The Safety Analysis set included all participants who received at least 1 dose of benralizumab.

End point type

Secondary

End point timeframe

At Weeks 16 and 48; and at early discontinuation or withdrawal visit

End point values	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-11 Years
Number of subjects analysed	15	15	15	13
Units: scores on a scale
PGIC-IA, Week 16, improved	13	13	13	12
PGIC-IA, Week 16, much improved	10	11	10	10
PGIC-IA, Week 16, very much improved	4	9	4	8
PGIC-IA, Week 48, improved	13	13	13	12
PGIC-IA, Week 48, much improved	9	11	9	10
PGIC-IA, Week 48, very much improved	9	10	9	9
CGIC, Week 16, improved	13	12	13	11
CGIC, Week 16, much improved	8	9	8	9
CGIC, Week 16, very much improved	3	5	3	5
CGIC, Week 48, improved	15	14	15	13
CGIC, Week 48, much improved	8	12	8	11
CGIC, Week 48, very much improved	5	6	5	6
CGIC = PGIC-IA, Week 16, improved	10	6	10	6
CGIC = PGIC-IA, Week 16, much improved	7	5	7	5
CGIC = PGIC-IA, Week 16, very much improved	3	4	3	4
CGIC = PGIC-IA, Week 48, improved	9	8	9	8
CGIC = PGIC-IA, Week 48, much improved	5	7	5	7
CGIC = PGIC-IA, Week 48, very much improved	5	6	5	6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment-emergent adverse events were collected from the start of study drug administration (Day 1) until end of follow-up, approximately up to Week 53

Adverse event reporting additional description

The Safety Analysis set consisted of all participants who received at least 1 dose of benralizumab.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Benralizumab Dose 1, Aged 6-11 Years

Reporting group description

Reporting group title

Benralizumab Dose 2, Aged 6-14 Years

Reporting group description

All participants with a body weight >=35 kg or aged 12-14 years (irrespective of body weight) at screening received benralizumab Dose 2 SC injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 2 at Weeks 24, 32, and 40 in Part B.

Reporting group title

Benralizumab Dose 1, Aged 6-14 Years

Reporting group description

All participants with a body weight <35 kg at screening received benralizumab Dose 1 SC injection once daily on Day 0 and at Weeks 4, 8, and 16 in Part A, followed by benralizumab Dose 1 at Weeks 24, 32, and 40 in Part B.

Reporting group title

Benralizumab Dose 2, Aged 6-11 Years

Reporting group description

Serious adverse events	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-11 Years
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 15 (6.67%)	4 / 15 (26.67%)	1 / 15 (6.67%)	2 / 13 (15.38%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 15 (6.67%)	4 / 15 (26.67%)	1 / 15 (6.67%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Somatic symptom disorder
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Benralizumab Dose 1, Aged 6-11 Years	Benralizumab Dose 2, Aged 6-14 Years	Benralizumab Dose 1, Aged 6-14 Years	Benralizumab Dose 2, Aged 6-11 Years
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 15 (86.67%)	11 / 15 (73.33%)	13 / 15 (86.67%)	9 / 13 (69.23%)
General disorders and administration site conditions
Vaccination site pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Pyrexia
subjects affected / exposed	3 / 15 (20.00%)	1 / 15 (6.67%)	3 / 15 (20.00%)	1 / 13 (7.69%)
occurrences all number	4	1	4	1
Injection site reaction
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	2	0	2	0
Fatigue
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Chills
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Immune system disorders
Allergy to animal
subjects affected / exposed	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 13 (7.69%)
occurrences all number	1	1	1	1
Immunisation reaction
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Cough
subjects affected / exposed	0 / 15 (0.00%)	3 / 15 (20.00%)	0 / 15 (0.00%)	3 / 13 (23.08%)
occurrences all number	0	3	0	3
Bronchitis chronic
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Nasal congestion
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Hyperventilation
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Upper-airway cough syndrome
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Wheezing
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Psychiatric disorders
Depression
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Panic attack
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Investigations
Occult blood positive
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Blood thyroid stimulating hormone decreased
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Ligament rupture
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Hand fracture
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Contusion
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	2	0	0
Nervous system disorders
Headache
subjects affected / exposed	2 / 15 (13.33%)	1 / 15 (6.67%)	2 / 15 (13.33%)	1 / 13 (7.69%)
occurrences all number	4	1	4	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Dental caries
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	3	0	3	0
Constipation
subjects affected / exposed	2 / 15 (13.33%)	1 / 15 (6.67%)	2 / 15 (13.33%)	0 / 13 (0.00%)
occurrences all number	2	1	2	0
Abdominal pain upper
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Abdominal pain
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Diarrhoea
subjects affected / exposed	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	2	0	1
Vomiting
subjects affected / exposed	2 / 15 (13.33%)	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 13 (0.00%)
occurrences all number	2	0	2	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Gastritis
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Dyspepsia
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	2	0	2
Skin and subcutaneous tissue disorders
Haemorrhage subcutaneous
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Eczema
subjects affected / exposed	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 13 (7.69%)
occurrences all number	1	1	1	1
Dermatitis atopic
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Asteatosis
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Urticaria
subjects affected / exposed	1 / 15 (6.67%)	2 / 15 (13.33%)	1 / 15 (6.67%)	1 / 13 (7.69%)
occurrences all number	1	2	1	1
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	2 / 15 (13.33%)	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 13 (0.00%)
occurrences all number	2	0	2	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Asymptomatic COVID-19
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	2 / 15 (13.33%)	2 / 15 (13.33%)	2 / 15 (13.33%)	2 / 13 (15.38%)
occurrences all number	2	3	2	3
Streptococcal infection
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Skin candida
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Sinusitis
subjects affected / exposed	2 / 15 (13.33%)	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 13 (0.00%)
occurrences all number	2	0	2	0
Pneumonia
subjects affected / exposed	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	2	0	1
Bronchitis bacterial
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Pharyngitis
subjects affected / exposed	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	2	1	0
Oral herpes
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
Nasopharyngitis
subjects affected / exposed	4 / 15 (26.67%)	2 / 15 (13.33%)	4 / 15 (26.67%)	1 / 13 (7.69%)
occurrences all number	5	3	5	1
Gastroenteritis
subjects affected / exposed	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0
COVID-19
subjects affected / exposed	1 / 15 (6.67%)	2 / 15 (13.33%)	1 / 15 (6.67%)	2 / 13 (15.38%)
occurrences all number	1	2	1	2
Pharyngitis streptococcal
subjects affected / exposed	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jul 2019

Amended to change table of assessments and synopsis. A cohort was added as per requirement by Japanese Regulatory Authority. Information regarding questionnaire assessments, body weight stratification, dosing, investigational product (IP) storage and packaging, time and date of blood sampling was updated. Information regarding the presence of nAb was deleted from the secondary objectives. Annualized asthma exacerbation rate was included as an exploratory objective. Information was added to clarify the risk related to hypersensitivity reactions; the requirements for participants in Part A and to describe the analysis of asthma exacerbation. Japanese Guidelines and definition of inhaled corticosteroid was implemented in the inclusion criteria. A prohibited medication was deleted as per team’s decision. Information on the Safety Review Committee was updated. A recommended sequence for the completion of assessments at each visit was added. A rationale was added for the completion of the ACQ-IA at all visits during the treatment and post-treatment periods. A description of the PGIC-IA and CGIC was added. References to liver enzyme elevations and to Hy’s Law were deleted. Reference to participants older than 9 years of age was deleted. The definition of participant evaluability was updated.

22 Aug 2019

Amended to change the synopsis. Clarification was added for the third cohort. Minor changes were added to clarify and improve text.

01 Jul 2020

Clarification was added on how the study could continue in the event of a serious disruption, including details of mitigations that could be employed to ensure study continuity. Updated inclusion criteria. The minimum observation time following IP administration was updated. The study period during which the use of live attenuated vaccines was prohibited was updated. Criteria for discontinuation was updated. The procedure for performing a forced expiratory maneuver in children aged <10 years was clarified. Procedures for hepatitis B surface antigen screening were updated.

22 Feb 2022

Estimated date of last participant completed was changed from May 2022 to September 2022. The minimum observation period at the clinical site following IP administration was changed to 1 hour from 2 hours. Aligned information presented with current protocol template. Clarification that electrocardiogram readings could be stored as physical copies in participant’s source files. New sections were added to discuss device constituent deficiencies in line with new European Union/United States regulations.

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: An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children with Severe Eosinophilic Asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Clearance of Benralizumab

Primary: Clearance of Benralizumab

Primary: Area Under the Serum Concentration-Time Curve From Time Zero to Day 28 (AUC0-28) of Benralizumab

Primary: Area Under the Serum Concentration-Time Curve From Time Zero to Day 28 (AUC0-28) of Benralizumab

Primary: Maximum Observed Serum Concentration (Cmax) of Benralizumab

Primary: Maximum Observed Serum Concentration (Cmax) of Benralizumab

Primary: Time to Achieve Maximum Observed Serum Concentration (tmax) of Benralizumab

Primary: Time to Achieve Maximum Observed Serum Concentration (tmax) of Benralizumab

Primary: Terminal Phase Elimination Half-Life (t1/2) of Benralizumab

Primary: Terminal Phase Elimination Half-Life (t1/2) of Benralizumab

Primary: Trough Concentration of Benralizumab at Week 16 (Ctrough16)

Primary: Trough Concentration of Benralizumab at Week 16 (Ctrough16)

Primary: Change From Baseline in Peripheral Blood Eosinophil Count up to Week 48

Primary: Change From Baseline in Peripheral Blood Eosinophil Count up to Week 48

Secondary: Body Weight-Adjusted Clearance of Benralizumab

Secondary: Body Weight-Adjusted Clearance of Benralizumab

Secondary: Number of Participants With Anti-Drug Antibodies (ADA) Response to Benralizumab

Secondary: Number of Participants With Anti-Drug Antibodies (ADA) Response to Benralizumab

Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) up to Week 48

Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) up to Week 48

Secondary: Change From Baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) Score up to Week 48

Secondary: Change From Baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) Score up to Week 48

Secondary: Number of Responders in Interviewer-Administered Patient Global Impression of Change (PGIC)-IA and Clinician Global Impression of Change (CGIC) Responder Status Questionnaires

Secondary: Number of Responders in Interviewer-Administered Patient Global Impression of Change (PGIC)-IA and Clinician Global Impression of Change (CGIC) Responder Status Questionnaires

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children with Severe Eosinophilic Asthma