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Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients with Mild to Moderate Persistent Asthma

Summary
EudraCT number	2014-004427-40
Trial protocol	SK DE HU
Global end of trial date	07 Oct 2015

Results information
Results version number	v1(current)
This version publication date	15 Oct 2016
First version publication date	15 Oct 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

D3250C00032

ISRCTN number

US NCT number

NCT02322775

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca Research and Development

Sponsor organisation address

One MedImmune Way, Gaithersburg, United States, MD 20878

Public contact

Mitchell Goldman, Global Clinical Leader Benralizumab, AstraZeneca Research and Development, +1 301 398 0323, Mitchell.Goldman@astrazeneca.com

Scientific contact

Mitchell Goldman, Global Clinical Leader Benralizumab, AstraZeneca Research and Development, +1 301 398 0323, Mitchell.Goldman@astrazeneca.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

03 Feb 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Oct 2015

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to evaluate the effect of benralizumab on pulmonary function in mild to moderate asthmatic patients.

Protection of trial subjects

The Informed Consent Form (ICF) incorporated or, in some cases, was accompanied by a separate document incorporating wording that complies with relevant data protection and privacy legislation. The Principal Investigator(s) at each study center ensured: • Each patient or legal guardian was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study (before any study procedures were performed) as per local requirements. The ICF needed to be adjusted as per local requirements. • Each patient or legal guardian was notified that they were free to discontinue from the study at any time. • That each patient or legal guardian was given the opportunity to ask questions and allowed time to consider the information provided. • Each patient or legal guardian provides signed and dated Informed Consent before conducting any procedure specifically for the study. • The original, signed Informed Consent(s) was/were stored in the Investigator’s Study File and kept for a period that is complaint with GCP/local regulatory requirements, whichever is longer. • A copy of the signed Informed Consent Form was given to the patient. • That any incentives for patients who participate in the study as well as any provisions for patients harmed as a consequence of study participation were described in the Informed Consent Form that is approved by an Ethics Committee.

Background therapy

At the time of screening/run-in, all patients, irrespective of their previous background therapy, were converted to either 180 or 200 μg dry powder inhaler twice daily (based on what was approved in the country where the study site was located) for the duration of the study. Changes to the patient’s background controller regimen were discouraged during the study unless judged medically necessary by the Investigator; such changes were discussed with the AstraZeneca Study Physician. All changes in the patient’s background medication were documented in source along with rational for change and recorded in eCRF.

Evidence for comparator

Matching placebo solution for injection in an accessorized pre-filled syringe (PFS) was administered at the study center subcutaneously every 4 weeks for 3 doses (Week 0, Week 4, and Week 8).

Actual start date of recruitment

02 Feb 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Germany: 57

Country: Number of subjects enrolled

Hungary: 40

Country: Number of subjects enrolled

Poland: 25

Country: Number of subjects enrolled

Slovakia: 19

Country: Number of subjects enrolled

United States: 52

Worldwide total number of subjects

211

EEA total number of subjects

141

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)

182

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

After enrollment, eligible patients entered a 2- to 4-week screening/run-in period and were converted to budesonide dry powder inhaler twice daily for the duration of the study. Patients who continued to meet eligibility criteria at the end of the run-in period entered a 12 weeks double-blind treatment period followed by two follow-up visits.

Screening details

Eligible adult patients were stratified by baseline blood eosinophil count (<300 cells/μL or ≥300 cells/μL) and by region (USA versus Rest of the World per the IVRS). Patients were then randomized to either benralizumab 30 mg Q4W or placebo in a 1:1 ratio. 351 patients were enrolled (informed consent received) and 211 were randomized.

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, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Benralizumab 30 mg Q4W

Arm description

Benralizumab administered subcutaneously every 4 weeks

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Benralizumab 30 mg/mL solution for injection administered at the study center SC every 4 weeks for 3 doses

Placebo

Arm description

Placebo administered subcutaneously every 4 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Matching placebo solution for injection administered at the study center SC every 4 weeks for 3 doses

Number of subjects in period 1	Benralizumab 30 mg Q4W	Placebo
Started	106	105
Completed	101	99
Not completed	5	6
Consent withdrawn by subject	3	4
Not willing to perform all FU visits	-	1
Adverse event, non-fatal	1	-
Lost to follow-up	-	1
Protocol deviation	1	-

Baseline characteristics

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Reporting group title

Benralizumab 30 mg Q4W

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously every 4 weeks

Reporting group values	Benralizumab 30 mg Q4W	Placebo	Total
Number of subjects	106	105	211
Age categorical
Units: Subjects
Adults (18-64 years)	92	90	182
From 65-75 years	14	15	29
Age Continuous \|
Units: Years
arithmetic mean (standard deviation)	48.3 ± 14.4	51.1 ± 12.6	-
Gender, Male/Female
Units: Participants
Female	62	67	129
Male	44	38	82
Age, Customized
Units: Subjects
>=18-<50	49	44	93
>=50-<65	43	46	89
>=65-<=75	14	15	29
Race/Ethnicity, Customized
Units: Subjects
Asian	1	0	1
Black or African American	7	4	11
White	98	99	197
Other	0	2	2
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	6	3	9
Not Hispanic or Latino	100	102	202

End points

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Reporting group title

Benralizumab 30 mg Q4W

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously every 4 weeks

Primary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

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End point title

Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

End point description

The changes from baseline in pre-bronchodilator FEV1 (L) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment*visit interaction as fixed effects and baseline pre-bronchodilator FEV1 (L) as a covariate.

End point type

Primary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	102 ^[1]	104 ^[2]
Units: Litre
arithmetic mean (standard deviation)
Baseline	2.248 ± 0.6062	2.246 ± 0.7677
Week 12	2.31 ± 0.6702	2.261 ± 0.7959
Change from baseline at Week 12	0.057 ± 0.2734	-0.016 ± 0.235

Notes
[1] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[2] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in pre-BD FEV1

Statistical analysis description

The null hypothesis was: H0: Change from baseline in pre-bronchodilator FEV1 (L) at Week 12 (benralizumab vs placebo)=0.

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04 ^[3]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.15

Notes
[3] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

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End point title

Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

End point description

Home morning PEF (L/min) weekly means were calculated using daily diary entries. The changes from baseline in weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline morning PEF (L/min) as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	104 ^[4]	104 ^[5]
Units: L/min
arithmetic mean (standard deviation)
Baseline	307.413 ± 95.9467	308.226 ± 113.5895
Week 12	311.041 ± 101.8169	304.037 ± 113.2538
Change from baseline at Week 12	1.675 ± 56.5182	-6.196 ± 45.3077

Notes
[4] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[5] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in morning PEF

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.233 ^[6]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

8.84

Confidence interval

level

95%

sides

2-sided

lower limit

-5.74

upper limit

23.42

Notes
[6] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

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End point title

Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

End point description

Home evening PEF (L/min) weekly means were calculated using daily diary entries. The outcome variable for evening PEF (L/min) was the change from baseline at Week 12 in weekly average of evening PEF (L/min). The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline evening PEF (L/min) as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	104 ^[7]	105 ^[8]
Units: L/min
arithmetic mean (standard deviation)
Baseline	326.948 ± 97.4034	316.743 ± 116.6919
Week 12	330.719 ± 106.7579	316.047 ± 118.7
Change from baseline at Week 12	1.361 ± 51.9979	-2.956 ± 47.9136

Notes
[7] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[8] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in evening PEF

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.456 ^[9]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

5.29

Confidence interval

level

95%

sides

2-sided

lower limit

-8.67

upper limit

19.25

Notes
[9] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in total asthma symptom score at Week 12

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End point title

Change from baseline in total asthma symptom score at Week 12

End point description

Asthma symptoms were recorded by the patient each morning and evening in the asthma daily diary. Symptoms were recorded using a scale of 0-3, where 0 indicates no asthma symptoms. The daily asthma symptom total score was calculated by taking the sum of the daytime score recorded in the evening and the nighttime score recorded the following morning. The outcome variable for total asthma score was change from baseline at Week 12 in weekly total asthma score. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma score as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	104 ^[10]	105 ^[11]
Units: Point scale
arithmetic mean (standard deviation)
Baseline	1.934 ± 0.931	1.952 ± 1.0375
Week 12	1.326 ± 1.0448	1.541 ± 1.1208
Change from baseline at Week 12	-0.567 ± 0.7875	-0.42 ± 0.8767

Notes
[10] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[11] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in total asthma score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.266 ^[12]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.1

Notes
[12] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in total asthma rescue medication use (puffs) at Week 12

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End point title

Change from baseline in total asthma rescue medication use (puffs) at Week 12

End point description

The number of rescue medication inhalations and nebulizer treatments taken were recorded by the patient in the asthma daily diary twice daily. The number of inhalations (puffs) per day was calculated as [number of night inhaler puffs] + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number of day nebulizer times]. The outcome variable for total asthma rescue medication use (puffs) was change from baseline at Week 12 in weekly total asthma rescue medication use (puffs). The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma rescue medication use (puffs) as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	105 ^[13]	105 ^[14]
Units: Puffs
arithmetic mean (standard deviation)
Baseline	2.953 ± 3.0794	2.641 ± 3.0671
Week 12	1.647 ± 2.4782	2.07 ± 2.6848
Change from baseline at Week 12	-1.098 ± 2.3588	-0.665 ± 2.2744

Notes
[13] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[14] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in total resc med use

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

210

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2 ^[15]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

0.19

Notes
[15] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in proportion of nights with nocturnal awakenings at Week 12

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End point title

Change from baseline in proportion of nights with nocturnal awakenings at Week 12

End point description

Nocturnal awakenings due to asthma symptoms and requiring rescue medication use was recorded by the patient in the asthma daily diary each morning. Proportion of nights with nocturnal awakenings was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data for awakening due to asthma. The outcome variable for proportion of nights with nocturnal awakenings was change from baseline at Week 12 in weekly proportion of nights with nocturnal awakenings. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline proportion of nights with nocturnal awakenings as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	105 ^[16]	105 ^[17]
Units: Proportion
arithmetic mean (standard deviation)
Baseline	0.246 ± 0.2924	0.279 ± 0.3326
Week 12	0.086 ± 0.2003	0.144 ± 0.2796
Change from baseline at Week 12	-0.158 ± 0.2515	-0.139 ± 0.2659

Notes
[16] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[17] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in prop of noct awak

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

210

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.38 ^[18]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.08

upper limit

0.03

Notes
[18] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Change from baseline in mean ACQ-6 score at Week 12

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End point title

Change from baseline in mean ACQ-6 score at Week 12

End point description

The asthma control questionnaire, ACQ-6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. The outcome variable for ACQ-6 score was change from baseline at Week 12. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment*visit interaction as fixed effects and baseline ACQ-6 score as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	104 ^[19]	104 ^[20]
Units: Point scale
arithmetic mean (standard deviation)
Baseline	2.119 ± 0.8423	2.092 ± 0.8975
Week 12	1.428 ± 0.8621	1.568 ± 1.009
Change from baseline at Week 12	-0.714 ± 0.87	-0.495 ± 0.7908

Notes
[19] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.
[20] - Number of subjects analyzed is the number of subjects included in the MMRM analyses.

Treatment comparisons of CFB in ACQ-6 score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.114 ^[21]

Method

Mixed models analysis

Parameter type

Difference of Least Square Means

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

0.04

Notes
[21] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Asthma exacerbations

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End point title

Asthma exacerbations

End point description

An asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for at least 3 days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids) or an emergency room or urgent care visit (defined as evaluation and treatment for <24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above) or an inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. Number of patients experiencing an event included in the definition of asthma exacerbation was presented.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	106	105
Units: Patients per number of exacerbations
= 0	105	103
= 1	0	2
= 2	1	0

No statistical analyses for this end point

Secondary: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

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End point title

Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

End point description

The asthma quality of life questionnaire for 12 years and older, AQLQ(S)+12, consists of 32 questions; all assessed on a 7-point scale from 7 to 1, where 7 represents no impairment and 1 represents severe impairment. The 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains. The overall score is calculated as the mean response to all questions. The outcome variable for AQLQ(S)+12 score was change from baseline at Week 12. The changes are compared between benralizumab 30 mg Q4W and placebo by using the analyse of covariance (ANCOVA) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL) and region (Europe or North America) as fixed effects and baseline AQLQ(S)+12 score as a covariate.

End point type

Secondary

End point timeframe

Up to Week 12

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	102 ^[22]	102 ^[23]
Units: Point scale
arithmetic mean (standard deviation)
Total score - Baseline	4.825 ± 0.9787	4.895 ± 1.0339
Total score - W12	5.415 ± 0.9478	5.284 ± 1.0851
Total score - CFB at W12	0.585 ± 0.8675	0.357 ± 0.7979
Symptoms score - Baseline	4.649 ± 1.0367	4.692 ± 1.083
Symptoms score - W12	5.38 ± 1.0076	5.212 ± 1.1373
Symptoms score - CFB at W12	0.727 ± 0.989	0.483 ± 0.9243
Activity limitations score - Baseline	5.017 ± 1.0029	5.048 ± 1.0277
Activity limitations score - W12	5.503 ± 0.9672	5.343 ± 1.0803
Activity limitations score - CFB at W12	0.481 ± 0.8156	0.275 ± 0.8105
Emotional function score - Baseline	4.95 ± 1.277	5.04 ± 1.373
Emotional function score - W12	5.54 ± 1.215	5.45 ± 1.307
Emotional function score - CFB at W12	0.57 ± 1.094	0.35 ± 1.014
Environmental stimuli score - Baseline	4.658 ± 1.332	4.905 ± 1.3554
Environmental stimuli score - W12	5.12 ± 1.291	5.13 ± 1.3372
Environmental stimuli score - CFB at W12	0.466 ± 1.0135	0.216 ± 0.9505

Notes
[22] - Number of subjects analyzed is the number of subjects included in the ANCOVA analyses.
[23] - Number of subjects analyzed is the number of subjects included in the ANCOVA analyses.

Treatment comparisons of CFB in total score

Statistical analysis description

Parameter: Total score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.055 ^[24]

Method

ANCOVA

Parameter type

Difference of Least Square Means

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.42

Notes
[24] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Treatment comparisons of CFB in symptoms score

Statistical analysis description

Parameter: Symptoms score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063 ^[25]

Method

ANCOVA

Parameter type

Difference of Least Square Means

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.47

Notes
[25] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Treatment comparisons of CFB in act. limit. score

Statistical analysis description

Parameter: Activity limitation score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.061 ^[26]

Method

ANCOVA

Parameter type

Difference of Least Square Means

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.41

Notes
[26] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Treatment comparisons of CFB in emot. funct. score

Statistical analysis description

Parameter: Emotional function score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.156 ^[27]

Method

ANCOVA

Parameter type

Difference of Least Square Means

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.45

Notes
[27] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Treatment comparisons of CFB in envir. stim. score

Statistical analysis description

Parameter: Environmental stimuli score

Comparison groups

Benralizumab 30 mg Q4W v Placebo

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.135 ^[28]

Method

ANCOVA

Parameter type

Difference of Least Square Means

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.44

Notes
[28] - Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).

Secondary: Serum Concentrations (ng/mL)

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End point title

Serum Concentrations (ng/mL)

End point description

Blood samples (processed to serum) for pharmacokinetic assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Serum concentrations of benralizumab were determined using a validated electrochemiluminescent (ECL) immunoassay.

End point type

Secondary

End point timeframe

Up to week 20

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	103	0 ^[29]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Week 12	999.16 ± 95.53	±
Week 20	59.04 ± 317.71	±

Notes
[29] - All Placebo patients had concentration below the limit of quantification (3.86 ng/mL).

No statistical analyses for this end point

Secondary: Peripheral blood eosinophil levels

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End point title

Peripheral blood eosinophil levels

End point description

Peripheral blood eosinophil levels assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit.

End point type

Secondary

End point timeframe

Up to Week 20

End point values	Benralizumab 30 mg Q4W	Placebo
Number of subjects analysed	106	105
Units: Cells/µL
median (full range (min-max))
Baseline	170 (30 to 1060)	220 (40 to 1140)
Week 12	0 (0 to 110)	230 (30 to 1000)
Change from baseline at Week 12	-170 (-1060 to 40)	10 (-710 to 910)
Week 20	0 (0 to 490)	210 (40 to 1440)
Change from Baseline at Week 20	-160 (-1060 to 130)	10 (-400 to 910)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs, including SAEs, in the on-study period were defined as those with onset between day of the first dose of study treatment and last scheduled follow-up visit, inclusive.

Adverse event reporting additional description

The safety analysis set comprised all patients who received at least one dose of IP. Patients were classified according to the treatment they actually received. A patient who has on one or several occasions received active treatment was classified as active. No subject received wrong dose in the study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously every 4 weeks

Reporting group title

Benralizumab 30 mg Q4W

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Serious adverse events	Placebo	Benralizumab 30 mg Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 105 (1.90%)	2 / 106 (1.89%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma
subjects affected / exposed	1 / 105 (0.95%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 105 (0.95%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 105 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 105 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Placebo	Benralizumab 30 mg Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 105 (13.33%)	19 / 106 (17.92%)
Nervous system disorders
Headache
subjects affected / exposed	1 / 105 (0.95%)	4 / 106 (3.77%)
occurrences all number	1	7
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 105 (2.86%)	4 / 106 (3.77%)
occurrences all number	3	4
Infections and infestations
Nasopharyngitis
subjects affected / exposed	8 / 105 (7.62%)	8 / 106 (7.55%)
occurrences all number	9	8
Upper respiratory tract infection
subjects affected / exposed	5 / 105 (4.76%)	5 / 106 (4.72%)
occurrences all number	5	5

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 Multicenter, Randomized, Double-blind, Parallel Group, Placebo controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients with Mild to Moderate Persistent Asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

Primary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

Secondary: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in total asthma symptom score at Week 12

Secondary: Change from baseline in total asthma symptom score at Week 12

Secondary: Change from baseline in total asthma rescue medication use (puffs) at Week 12

Secondary: Change from baseline in total asthma rescue medication use (puffs) at Week 12

Secondary: Change from baseline in proportion of nights with nocturnal awakenings at Week 12

Secondary: Change from baseline in proportion of nights with nocturnal awakenings at Week 12

Secondary: Change from baseline in mean ACQ-6 score at Week 12

Secondary: Change from baseline in mean ACQ-6 score at Week 12

Secondary: Asthma exacerbations

Secondary: Asthma exacerbations

Secondary: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Secondary: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Secondary: Serum Concentrations (ng/mL)

Secondary: Serum Concentrations (ng/mL)

Secondary: Peripheral blood eosinophil levels

Secondary: Peripheral blood eosinophil levels

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients with Mild to Moderate Persistent Asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

Primary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12

Secondary: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

Secondary: Change from baseline in total asthma symptom score at Week 12

Secondary: Change from baseline in total asthma symptom score at Week 12

Secondary: Change from baseline in total asthma rescue medication use (puffs) at Week 12

Secondary: Change from baseline in total asthma rescue medication use (puffs) at Week 12

Secondary: Change from baseline in proportion of nights with nocturnal awakenings at Week 12

Secondary: Change from baseline in proportion of nights with nocturnal awakenings at Week 12

Secondary: Change from baseline in mean ACQ-6 score at Week 12

Secondary: Change from baseline in mean ACQ-6 score at Week 12

Secondary: Asthma exacerbations

Secondary: Asthma exacerbations

Secondary: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Secondary: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Secondary: Serum Concentrations (ng/mL)

Secondary: Serum Concentrations (ng/mL)

Secondary: Peripheral blood eosinophil levels

Secondary: Peripheral blood eosinophil levels

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients with Mild to Moderate Persistent Asthma