Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients with Mild to Moderate Persistent Asthma

Study identifier:D3250C00032

ClinicalTrials.gov identifier:NCT02322775

EudraCT identifier:2014-004427-40

CTIS identifier:N/A

Study Complete

Official Title

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.

Medical condition

asthma

Phase

Phase 3

Healthy volunteers

Study drug

Sex

All

Actual Enrollment

211

Study type

Interventional

Age

18 Years - 75 Years

Date

Study Start Date: 02 Feb 2015

Primary Completion Date: 07 Oct 2015

Study Completion Date: 07 Oct 2015

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Aug 2017 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.
- Female and male aged 18 to 75 years, inclusively, at the time of Visit 1.
- Weight of ≥40 kg.
- Evidence of asthma as documented by post-bronchodilator (post-BD) reversibility in FEV1 of ≥ 12% demonstrated at Visit 2.
- Documented use of 1 of the following types of asthma therapy at time of informed consent: Low- to medium-dose ICS (ie, 100 to 500 μg fluticasone dry powder formulation equivalents total daily dose) with or without other controller medications, eg, an LTRA and/or theophylline or Low-dose ICS/LABA fixed combination therapy (eg, the lowest regular maintenance dose approved in the local country will meet this criterion)
- Morning pre-bronchodilator (pre-BD) FEV1 of > 50% to ≤ 90% predicted at Visit 2.

Exclusion Criteria

- Clinically important pulmonary disease other than asthma (eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
- Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:
- Affect the safety of the patient throughout the study
- nfluence the findings of the studies or their interpretations,- Impede the patient’s ability to complete the entire duration of study.
- Known history of allergy or reaction to the investigational product formulation.
- History of anaphylaxis to any biologic therapy.-
History of Guillain-Barré syndrome.
- A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.-
Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period.
- Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient’s ability to complete entire duration of the study.
- Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll.
- A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
- History of cancer:
- Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
- Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained

Location

Research Site

Frankfurt/Main, Germany, 60389

Location

Research Site

Berlin, Germany, 10787

Location

Research Site

Frankfurt, Germany, 60596

Location

Research Site

Neu-Isenburg, Germany, 63263

Location

Research Site

Hannover, Germany, 30173

Location

Research Site

Bamberg, Germany, 96049

Location

Research Site

Quebec, QC, Canada, G1G 3Y8

Location

Research Site

Vancouver, BC, Canada, V5Z 1M9

Arms	Assigned Interventions
Experimental: Arm A Benralizumab administered subcutaneously every 4 weeks	Biological/Vaccine: Benralizumab Benralizumab administered subcutaneously every 4 weeks Other Name: Benralizumab
Experimental: Arm B Placebo administered subcutaneously every 4 weeks	Biological/Vaccine: Placebo Placebo administered subcutaneously every 4 weeks Other Name: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Participant Flow: Overall Study

	Benralizumab 30 mg Q4W	Placebo
STARTED	106	105
COMPLETED	101	99
NOT COMPLETED	5	6
Adverse Event	1	0
Lost to Follow-up	0	1
Protocol Violation	1	0
Withdrawal by Subject	3	4
Not willing to perform all FU visits	0	1

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Baseline Measures

	Benralizumab 30 mg Q4W	Placebo	Total
Number of Participants [units: Participants]	106	105	211
Age Continuous [units: Years] Mean ± Standard Deviation	48.3 ± 14.40	51.1 ± 12.60	49.7 ± 13.58
Age, Customized [units: Participants]
>=18-<50 years	49	44	93
>=50-<65 years	43	46	89
>=65-<=75 years	14	15	29
Gender, Male/Female [units: Participants]
Female	62	67	129
Male	44	38	82
Race/Ethnicity, Customized [units: Participants]
Asian	1	0	1
Black or African American	7	4	11
White	98	99	197
Other	0	2	2
Race/Ethnicity, Customized [units: Participants]
Hispanic or Latino	6	3	9
Not Hispanic or Latino	100	102	202

Outcome Measures

1. Primary Outcome Measure: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12 [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]

Measure Type	Primary
Measure Name	Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12
Measure Description	The FEV1 (L) change from baseline are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) analysis 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 4, Week 8 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) (L) at Week 12 [units: Litre] Mean (Standard Deviation)
Baseline	2.248 (0.6062)	2.246 (0.7677)
Week 12	2.310 (0.6702)	2.261 (0.7959)
Change from baseline at Week 12	0.057 (0.2734)	-0.016 (0.2350)

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

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.040
Other^[5]	0.08
95% Confidence Interval	( 0 to 0.15 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis was: H0: Change from baseline in pre-bronchodilator FEV1 (L) at Week 12 (benralizumab vs placebo)=0.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12
Measure Description	The changes from baseline of weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12 [units: L/min] 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)

Statistical Analysis 1 for Change from baseline in morning peak expiratory flow (PEF) (L/min) at home at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.233
Other^[5]	8.84
95% Confidence Interval	( -5.74 to 23.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12
Measure Description	The changes from baseline of weekly average of evening PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12 [units: L/min] Mean (Standard Deviation)
Baseline	326.948 (97.4034)	316.743 (116.6919)
Week 12	330.719 (106.7579)	316.047 (118.7000)
Change from baseline at Week 12	1.361 (51.9979)	-2.956 (47.9136)

Statistical Analysis 1 for Change from baseline in evening peak expiratory flow (PEF) (L/min) at home at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.456
Other^[5]	5.29
95% Confidence Interval	( -8.67 to 19.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Change from baseline in total asthma symptom score at Week 12 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in total asthma symptom score at Week 12
Measure 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 weekly total asthma score was averaged from the daily scores over a 7 day period, with score ranging from 0 to 6, where 0 indicates no asthma symptoms. The changes from baseline of weekly total asthma score 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in total asthma symptom score at Week 12 [units: Scores on a scale] Mean (Standard Deviation)
Baseline	1.934 (0.9310)	1.952 (1.0375)
Week 12	1.326 (1.0448)	1.541 (1.1208)
Change from baseline at Week 12	-0.567 (0.7875)	-0.420 (0.8767)

Statistical Analysis 1 for Change from baseline in total asthma symptom score at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.266
Other^[5]	-0.13
95% Confidence Interval	( -0.35 to 0.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Change from baseline in total asthma rescue medication use (puffs) at Week 12 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in total asthma rescue medication use (puffs) at Week 12
Measure 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 changes from baseline in weekly total asthma rescue medication use (puffs) 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in total asthma rescue medication use (puffs) at Week 12 [units: Puffs per day] Mean (Standard Deviation)
Baseline	2.953 (3.0794)	2.641 (3.0671)
Week 12	1.647 (2.4782)	2.070 (2.6848)
Change from baseline at Week 12	-1.098 (2.3588)	-0.665 (2.2744)

Statistical Analysis 1 for Change from baseline in total asthma rescue medication use (puffs) at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.200
Other^[5]	-0.36
95% Confidence Interval	( -0.91 to 0.19 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Change from baseline in proportion of nights with nocturnal awakenings at Week 12 [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in proportion of nights with nocturnal awakenings at Week 12
Measure 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 the 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in proportion of nights with nocturnal awakenings at Week 12 [units: Proportion of nights] 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)

Statistical Analysis 1 for Change from baseline in proportion of nights with nocturnal awakenings at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.380
Other^[5]	-0.03
95% Confidence Interval	( -0.08 to 0.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Change from baseline in mean ACQ-6 score at Week 12 [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in mean ACQ-6 score at Week 12
Measure 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 changes from baseline of ACQ-6 score 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline, Week 4, Week 8 and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in mean ACQ-6 score at Week 12 [units: Scores on a scale] Mean (Standard Deviation)
Baseline	2.119 (0.8423)	2.092 (0.8975)
Week 12	1.428 (0.8621)	1.568 (1.0090)
Change from baseline at Week 12	-0.714 (0.8700)	-0.495 (0.7908)

Statistical Analysis 1 for Change from baseline in mean ACQ-6 score at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.114
Other^[5]	-0.17
95% Confidence Interval	( -0.39 to 0.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Asthma exacerbations [ Time Frame: Up to Week 12 ]

Measure Type	Secondary
Measure Name	Asthma exacerbations
Measure 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.
Time Frame	Up to Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Asthma exacerbations [units: Patients per number of exacerbations]
0 exacerbation	105	103
1 exacerbation	0	2
2 exacerbations	1	0

No statistical analysis provided for Asthma exacerbations

9. Secondary Outcome Measure: Change from baseline in AQLQ(S)+12 total and domain scores at Week 12 [ Time Frame: Baseline and Week 12 ]

Measure Type	Secondary
Measure Name	Change from baseline in AQLQ(S)+12 total and domain scores at Week 12
Measure 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 changes from baseline of AQLQ(S)+12 score 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. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time Frame	Baseline and Week 12
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Change from baseline in AQLQ(S)+12 total and domain scores at Week 12 [units: Scores on a scale] 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 (1.0830)
Symptoms score - W12	5.380 (1.0076)	5.212 (1.1373)
Symptoms score - CFB at W12	0.727 (0.9890)	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 (1.3320)	4.905 (1.3554)
Environmental stimuli score - W12	5.120 (1.2910)	5.130 (1.3372)
Environmental stimuli score - CFB at W12	0.466 (1.0135)	0.216 (0.9505)

Statistical Analysis 1 for Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.055
Other^[5]	0.21
95% Confidence Interval	( 0 to 0.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Parameter: Total score
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.063
Other^[5]	0.23
95% Confidence Interval	( -0.01 to 0.47 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Parameter: Symptoms score
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.061
Other^[5]	0.20
95% Confidence Interval	( -0.01 to 0.41 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Parameter: Activity limitation score
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.156
Other^[5]	0.19
95% Confidence Interval	( -0.07 to 0.45 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Parameter: Emotional function score
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Change from baseline in AQLQ(S)+12 total and domain scores at Week 12

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.135
Other^[5]	0.19
95% Confidence Interval	( -0.06 to 0.44 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Parameter: Environmental stimuli score
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypothesis testing were reported using 2-sided 5% level tests with nominal p-values (i.e., not adjusted for multiplicity).
[5]	Other relevant estimation information:
	No text entered.

10. Secondary Outcome Measure: Serum Concentrations (ng/mL) [ Time Frame: Baseline, Week 12 and Week 20 ]

Measure Type	Secondary
Measure Name	Serum Concentrations (ng/mL)
Measure 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.
Time Frame	Baseline, Week 12 and Week 20
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic (PK) analysis set comprised all patients who received benralizumab and from whom PK blood samples were obtained are assumed not to be affected by factors such as protocol violations. Those patients who had at least 1 quantifiable serum PK observation post first dose were included in the PK analysis dataset.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	103	0
Serum Concentrations (ng/mL) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Pre- 1st dose	NA (NA%)^[1]
Week 12	999.16 (95.53%)
Week 20	59.04 (317.71%)

[1]	All patients had concentration below the limit of quantification (3.86 ng/mL).

No statistical analysis provided for Serum Concentrations (ng/mL)

11. Secondary Outcome Measure: Peripheral blood eosinophil levels [ Time Frame: Baseline, Week 12 and Week 20 ]

Measure Type	Secondary
Measure Name	Peripheral blood eosinophil levels
Measure 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. Changes at Week 12 (respectively at Week 20) were calculated based on patients with both baseline and Week 12 (respectively Week 20).
Time Frame	Baseline, Week 12 and Week 20
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Measured Values

	Benralizumab 30 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	106	105
Peripheral blood eosinophil levels [units: Cells/µL] Median (Full Range)
Baseline	170 (30 to 1060)	220 (40 to 1140)
Week 12	0.00 (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 analysis provided for Peripheral blood eosinophil levels

Serious Adverse Events

Time Frame	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, up to 20 weeks.
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.

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Serious Adverse Events

Benralizumab 30 mg Q4W

Placebo

Total, serious adverse events

# participants affected / at risk

2/106 (1.89%)

2/105 (1.90%)

Blood and lymphatic system disorders

Pancytopenia¹,^†

# participants affected / at risk

1/106 (0.94%)

0/105 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Cervix carcinoma¹,^†

# participants affected / at risk

0/106 (0.00%)

1/105 (0.95%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Colon adenoma¹,^†

# participants affected / at risk

0/106 (0.00%)

1/105 (0.95%)

# events

Psychiatric disorders

Suicide attempt¹,^†

# participants affected / at risk

1/106 (0.94%)

0/105 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Other Adverse Events

Time Frame	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, up to 20 weeks.
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.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Benralizumab 30 mg Q4W	Benralizumab administered subcutaneously every 4 weeks
Placebo	Placebo administered subcutaneously every 4 weeks

Other Adverse Events

Benralizumab 30 mg Q4W

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

19/106 (17.92%)

14/105 (13.33%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

8/106 (7.55%)

8/105 (7.62%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

5/106 (4.72%)

5/105 (4.76%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

4/106 (3.77%)

1/105 (0.95%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

4/106 (3.77%)

3/105 (2.86%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: ≥ 60 days prior to submission of material for publication/presentation, Institution and PI shall jointly provide AZ with material for review. No publication/presentation may include any of AZ’s Confidential Information without AZ’s written approval. AZ can request Inst. and PI to withhold material from submission for publication/presentation for an additional 90 days to allow AZ to establish and preserve its proprietary rights in the material being submitted for publication or presentation.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Mitchell Goldman, Global Clinical Leader Benralizumab
Organization:	AstraZeneca Research and Development
Phone	301 398 0323 Ext: +1
E-mail:	[email protected]

Documents available

CSP redacted
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

AstraZeneca Clinical Study Information

+1 800-236

information.center@astrazeneca.com

Investigators

Principal Investigator

Gary T. Ferguson

Pulmonary Research Institute of Southeast Michigan

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSP redacted

Trial Results Summaries