Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist

• ClinicalTrials.gov Identifier: NCT01914757
• Recruitment Status: Completed
• First Posted: August 2, 2013
• Results First Posted: January 25, 2017
• Last Update Posted: January 25, 2017
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Asthma
• Interventions: Biological: Benralizumab; Biological: Placebo
• Enrollment: 2508

Participant Flow

Recruitment Details
Pre-assignment Details	2505 participants signed informed consent, 2181 entered screening/run-in period, 1306 participants were randomised to receive treatment with benralizumab 30 mg Q4W, Q8W, or placebo. Of the 1306 patients randomised, all (100.0%) received treatment with study drug.

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Period Title: Overall Study
Started	425	441	440
Completed	389	390	402
Not Completed	36	51	38
Reason Not Completed
Severe non-compliance to protocol	3	1	2
Lost to Follow-up	5	8	6
Withdrawal by Subject	15	27	19
Death	2	2	1
Adverse Event	4	3	4
Study specific withdrawal criteria	0	1	0
Eligibility criteria not fulfilled	2	0	2
Other reasons	5	9	4

Baseline Characteristics

Arm/Group Title		Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo	Total
Arm/Group Description		Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously	Total of all reporting groups
Overall Number of Baseline Participants		425	441	440	1306
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	425 participants	441 participants	440 participants	1306 participants
		50.0 (13.6)	49 (14.3)	48.8 (15.1)	49.2 (14.3)
Gender; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	425 participants	441 participants	440 participants	1306 participants
	Female	270 63.5%	273 61.9%	264 60.0%	807 61.8%
	Male	155 36.5%	168 38.1%	176 40.0%	499 38.2%

Outcome Measures

1. Primary Outcome

Title	Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils >=300/uL
Description	The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS.

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Least Squares Mean (95% Confidence Interval); Unit of Measure: Events/year
	0.6; (0.48 to 0.74)	0.66; (0.54 to 0.82)	0.93; (0.77 to 1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Negative Binomial
	Comments	Model includes covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.85
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	Negative Binomial
	Comments	Model includes covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.95
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils <300/uL
Description	The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils <300/uL, High-dose ICS.

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	116	125	122
Least Squares Mean (95% Confidence Interval); Unit of Measure: Events/year
	0.78; (0.59 to 1.02)	0.73; (0.55 to 0.95)	1.21; (0.96 to 1.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.015
	Comments	[Not Specified]
	Method	Negative Binomial
	Comments	Model includes covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.92
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.005
	Comments	[Not Specified]
	Method	Negative Binomial
	Comments	Model includes covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.86
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils >=300/uL
Description	[Not Specified]
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	216	211	221
Mean (Standard Deviation); Unit of Measure: Liter
	0.34 (0.469)	0.332 (0.518)	0.206 (0.471)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.005
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline pre-BD FEV1, region, use of OCS, visit, and treatment by visit
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.125
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.213
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline pre-BD FEV1, region, use of OCS, visit, and treatment by visit
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.116
	Confidence Interval	(2-Sided) 95%; 0.028 to 0.204
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils <300/uL
Description	[Not Specified]
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils <300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	101	98	99
Mean (Standard Deviation); Unit of Measure: Liter
	0.221 (0.441)	0.164 (0.358)	0.135 (0.437)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.268
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline pre-BD FEV1, region, use of OCS, visit, and treatment by visit
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; -0.049 to 0.176
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.786
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline pre-BD FEV1, region, use of OCS, visit, and treatment by visit
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.015
	Confidence Interval	(2-Sided) 95%; -0.127 to 0.096
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils >=300/uL
Description	Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	184	185	187
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-1.33 (1.23)	-1.4 (1.17)	-1.2 (1.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.224
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma symptom score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.07
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma symptom score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.04
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL
Description	Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils <300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	88	85	89
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-1.05 (1.14)	-0.95 (1.13)	-0.88 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.287
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma symptom score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.13
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.966
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma symptom score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.29
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Change in Asthma Rescue Medication Use
Description	Change from Baseline to Week 56 in number of Rescue medication use (puffs/day)
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	184	185	187
Mean (Standard Deviation); Unit of Measure: Puffs per day
	-2.0 (3.64)	-2.92 (3.60)	-2.65 (9.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.603
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma rescue medication use, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.99
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.209
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline Asthma medication use, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.29 to 0.28
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Home Lung Function Assessments Based on PEF
Description	Change from Baseline to Week 56 in Home lung function (morning and evening Peak expiratory flow [PEF])
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Mean (Standard Deviation); Unit of Measure: L/min
Change at Week 56, Morning (n=194, 193, 197)	41.745 (78.534)	43.375 (91.865)	23.961 (71.509)
Change at Week 56, Evening (n=194, 192, 197)	35.142 (75.489)	39.270 (89.772)	15.448 (78.341)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	Morning PEF Change from Baseline to Week 56
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.029
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline morning PEF, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	15.86
	Confidence Interval	(2-Sided) 95%; 1.59 to 30.12
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	Morning PEF Change from Baseline to Week 56
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.037
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline morning PEF, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	15.27
	Confidence Interval	(2-Sided) 95%; 0.9 to 29.64
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	Evening PEF Change from Baseline to Week 56
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.018
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline evening PEF, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	17.54
	Confidence Interval	(2-Sided) 95%; 3.07 to 32
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	Evening PEF Change from Baseline to Week 56
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline evening PEF, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.22
	Confidence Interval	(2-Sided) 95%; 6.65 to 35.79
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Proportion of Nights With Awakening Due to Asthma
Description	Change from Baseline to Week 56 on Proportion of Nights with awakening due to asthma
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	196	198	203
Mean (Standard Deviation); Unit of Measure: Proportion of nights
	-0.373 (0.388)	-0.431 (0.4)	-0.372 (0.405)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline prop of nights with nocturnal wakening, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.146
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline prop of nights with nocturnal wakening, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.01
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils >=300/uL
Description	ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	192	185	197
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-1.34 (1.13)	-1.49 (1.13)	-1.21 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.043
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline ACQ-6 score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.01
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.008
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline ACQ-6 score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.07
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils <300/uL
Description	ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils <300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	88	83	92
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	-1.22 (1.16)	-1.06 (1.02)	-0.83 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.078
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline ACQ-6 score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.449
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline ACQ-6 score, region, use of OCS, visit, and visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.16
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Number of Patients With >=1 Asthma Exacerbation
Description	[Not Specified]
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Measure Type: Number; Unit of Measure: Participants
	84	95	126

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	Proportion of patients with >=1 asthma exacerbation
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Controlling for region, number of exacerbations in the previous year, use of OCS
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.69
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	Proportion of patients with >=1 asthma exacerbation
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.023
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Controlling for region, number of exacerbations in the previous year, use of OCS
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.95
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Time to First Asthma Exacerbation
Description	[Not Specified]
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Measure Type: Number; Unit of Measure: Participants
	84	95	126

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	Time to first Exacerbation
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Model includes treatment, region, number of exacerbations in the previous year, use of OCS
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.80
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	Time to first asthma exacerbation
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.018
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Model includes treatment, region, number of exacerbations in the previous year, use of OCS
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.95
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Annual Rate of Asthma Exacerbation Resulting Emergency Room Visits and Hospitalizations
Description	Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization (adjudicated)
Time Frame	Immediately following the first administration of study drug through Study Week 56.

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Least Squares Mean (95% Confidence Interval); Unit of Measure: Events/year
	0.04; (0.02 to 0.06)	0.05; (0.03 to 0.08)	0.04; (0.02 to 0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.837
	Comments	[Not Specified]
	Method	negative binomial
	Comments	Model includes treatment, region, any prior exacerbation resulting ER/Hospitalization, use of OCS
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.82
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.538
	Comments	[Not Specified]
	Method	negative binomial
	Comments	Model includes treatment, region, any prior exacerbation resulting ER/Hospitalization, use of OCS
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.64 to 2.35
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Pharmacokinetics of Benralizumab
Description	Mean PK Concentration at each visit
Time Frame	Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	435	424	0
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Baseline (n=435, 419)	NA [1]; (NA%)	NA [1]; (NA%)
Week 4 (n=430, 416)	650.04; (154.61%)	703.16; (89.48%)
Week 8 (n=414, 395)	894.86; (148.91%)	939.45; (98.99%)
Week 16 (n=390, 378)	936.43; (247.46%)	252.54; (274.74%)
Week 24 (n=388, 361)	827.09; (370.64%)	188.99; (308.38%)
Week 32 (n=345, 323)	823.21; (362.43%)	166.53; (289.34%)
Week 40 (n=370, 338)	859.69; (364.28%)	172.28; (298.6%)
Week 48 (n=355, 337)	888.09; (333.98%)	186.5; (290.28%)
Week 56 (n=358, 344)	763.98; (309.18%)	173.41; (235.86%)
Week 60 (n=49, 45)	53.63; (1782.96%)	18.63; (756.47%)

[1]

Value is less than lower limit of quantification

16. Secondary Outcome

Title	Immunogenicity of Benralizumab
Description	Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post-baseline assessments (with >=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
Time Frame	Pre-treatment until end of follow-up

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	438	427	440
Measure Type: Number; Unit of Measure: Participants
Positive at any visit (n=438, 427, 440)	63	64	13
Base- and Post-baseline Postive (n=431, 414, 430)	5	5	5
Only post-baseline positive (n=431, 420, 436)	55	57	8
Persistently positive (n=431, 420, 436)	44	42	7
Transient positive (n=431, 420, 436)	16	20	6
Only baseline positive (n=438, 421, 434)	3	2	0

17. Secondary Outcome

Title	Extent of Exposure
Description	Extent of exposure is defined as the duration of treatment in days
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	438	428	440
Mean (Standard Deviation); Unit of Measure: Days
	344.14 (73.129)	331.64 (88.839)	336.69 (82.148)

18. Secondary Outcome

Title	Mean Change From Baseline to Week 56 in AQLQ(S)+12
Description	AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of >=0.5 are considered clinically meaningful.
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	186	180	191
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	1.44 (1.15)	1.61 (1.24)	1.32 (1.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.4 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.119
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline AQLQ score, region, use of OCS, visit, visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.37
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab 30 mg q.8 Weeks, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Model includes treatment, baseline AQLQ score, region, use of OCS, visit, visit by treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.45
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Change From Baseline to Week 56 in EQ-5D-5L VAS
Description	EQ-5D-5L VAS is to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state.
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	183	179	191
Mean (Standard Deviation); Unit of Measure: Scores on a scale
	13.8 (21.52)	15.5 (20.36)	12.1 (20.13)

20. Secondary Outcome

Title	Mean Work Productivity Loss Due to Asthma
Description	WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked. This is only applicable to patients who were employed.
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS, who were employed

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	92	74	85
Mean (Standard Deviation); Unit of Measure: Percent of productivity loss
	26.56 (25.589)	24.44 (24.689)	27.29 (25.802)

21. Secondary Outcome

Title	Mean Productivity Loss Due to Asthma in Classroom
Description	WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Classroom productivity loss is derived by sum of percentage of missed classes due to asthma and product of percentage of actual hours attending classes times degree of asthma affecting classroom productivity. Percentage of missed classes due to asthma is calculated by number of hours missed classes due to asthma divided by total number of hours missed classes plus number of hours actually attending classes. This is only applicable for patients who took classes.
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS, who took classes

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	14	5	5
Mean (Standard Deviation); Unit of Measure: percent of productivity loss
	19.92 (23.765)	14 (16.733)	33.5 (25.593)

22. Secondary Outcome

Title	Number of Participants That Utilized Health Care Resources
Description	[Not Specified]
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Measure Type: Number; Unit of Measure: Participants
Hospitalizations	11	14	12
Emergency department visits	11	12	18
Unscheduled outpatient visits	72	75	83
Home visits	3	1	2
Telephone calls	50	63	58
Ambulance transports	2	3	5

23. Secondary Outcome

Title	Patient and Clinician Assessment of Response to Treatment
Description	CGIC (clinician global impression of change), and PGIC (patient global impression of change) are overall evaluation of response to treatment, conducted separately by investigator and patient using a 7-point rating scale, ranging from 1 (Very much Improved), to 7 (Very much Worse). This endpoint was added after the second protocol amendment, thus not all patients had data to be analyzed.
Time Frame	Immediately following the first administration of study drug through Study Week 56

Outcome Measure Data

Analysis Population Description

Full analysis set, Baseline eosinophils >=300/uL, High-dose ICS

Arm/Group Title	Benralizumab 30 mg q.4 Weeks	Benralizumab 30 mg q.8 Weeks	Placebo
Arm/Group Description:	Benralizumab administered subcutaneously every 4 weeks	Benralizumab administered subcutaneously every 8 weeks	Placebo administered subcutaneously
Overall Number of Participants Analyzed	241	239	248
Measure Type: Number; Unit of Measure: Participants
CGIC, Improved	109	96	97
CGIC, Much Improved	82	71	65
CGIC, Very Much Improved	26	23	14
CGIC, Total	217	190	176
PGIC, Improved	109	95	99
PGIC, Much Improved	83	80	66
PGIC, Very Much Improved	34	30	17
PGIC, Total	226	205	182

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Benralizumab 30 mg q.4 Weeks		Benralizumab 30 mg q.8 Weeks		Placebo
Arm/Group Description	Benralizumab administered subcutaneously every 4 weeks		Benralizumab administered subcutaneously every 8 weeks		Placebo administered subcutaneously
All-Cause Mortality
	Benralizumab 30 mg q.4 Weeks		Benralizumab 30 mg q.8 Weeks		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	Benralizumab 30 mg q.4 Weeks		Benralizumab 30 mg q.8 Weeks		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/438 (10.50%)		41/428 (9.58%)		61/440 (13.86%)
Blood and lymphatic system disorders
Anaemia † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Cardiac disorders
Acute coronary syndrome † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Acute myocardial infarction † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	1/440 (0.23%)	2
Angina pectoris † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Aortic valve stenosis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Atrial fibrillation † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Atrioventricular block complete † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Cardiac arrest † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Cardiac failure congestive † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Coronary artery disease † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Myocardial infarction † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	1/440 (0.23%)	1
Myocardial ischaemia † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	2/440 (0.45%)	2
Supraventricular tachycardia † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Eye disorders
Cataract † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Gastrointestinal disorders
Gastritis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Gastroduodenitis † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Inguinal hernia † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Large intestine polyp † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Rectal polyp † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
General disorders
Chest pain † 1	1/438 (0.23%)	1	1/428 (0.23%)	1	0/440 (0.00%)	0
Death † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Non-cardiac chest pain † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Hepatobiliary disorders
Cholecystitis † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Cholecystitis acute † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Cholecystitis chronic † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Cholelithiasis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Hepatitis alcoholic † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Immune system disorders
Anaphylactic reaction † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Drug hypersensitivity † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	1/440 (0.23%)	1
Infections and infestations
Appendicitis † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Bacterial infection † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Bronchitis † 1	1/438 (0.23%)	1	1/428 (0.23%)	1	0/440 (0.00%)	0
Bronchitis haemophilus † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Chronic sinusitis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Cytomegalovirus hepatitis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Gastroenteritis † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Herpes zoster † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Influenza † 1	0/438 (0.00%)	0	2/428 (0.47%)	2	0/440 (0.00%)	0
Liver abscess † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Pneumonia † 1	2/438 (0.46%)	2	0/428 (0.00%)	0	4/440 (0.91%)	6
Pneumonia bacterial † 1	2/438 (0.46%)	2	0/428 (0.00%)	0	3/440 (0.68%)	3
Pseudomonas bronchitis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Pseudomonas infection † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Respiratory tract infection bacterial † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Sepsis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Sinusitis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Upper respiratory tract infection † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Urinary tract infection † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Injury, poisoning and procedural complications
Anastomotic ulcer † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Humerus fracture † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Injury † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Joint injury † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Patella fracture † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Procedural complication † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Road traffic accident † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Thermal burn † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Toxicity to various agents † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Metabolism and nutrition disorders
Obesity † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Dupuytren's contracture † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Epiphysiolysis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Intervertebral disc disorder † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	1/440 (0.23%)	1
Jaw cyst † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Muscular weakness † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Osteoarthritis † 1	1/438 (0.23%)	1	1/428 (0.23%)	1	1/440 (0.23%)	1
Rheumatoid arthritis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Rotator cuff syndrome † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Spinal osteoarthritis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Spondylolisthesis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer female † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Colon neoplasm † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Gallbladder cancer † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Gastric cancer † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Thyroid adenoma † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Uterine leiomyoma † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Nervous system disorders
Cerebrovascular accident † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Lumbar radiculopathy † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	2
Sciatica † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Seizure † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Syncope † 1	1/438 (0.23%)	1	1/428 (0.23%)	1	0/440 (0.00%)	0
Transient ischaemic attack † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Psychiatric disorders
Completed suicide † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Depression † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Renal and urinary disorders
Calculus ureteric † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Nephrolithiasis † 1	2/438 (0.46%)	3	0/428 (0.00%)	0	0/440 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Respiratory, thoracic and mediastinal disorders
Asthma † 1	21/438 (4.79%)	25	19/428 (4.44%)	27	23/440 (5.23%)	38
Hyperventilation † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Nasal polyps † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Nasal turbinate hypertrophy † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Pleural effusion † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Skin and subcutaneous tissue disorders
Parakeratosis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Urticaria † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Urticaria papular † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	0/440 (0.00%)	0
Vascular disorders
Aortic stenosis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Hypertension † 1	0/438 (0.00%)	0	1/428 (0.23%)	1	1/440 (0.23%)	1
Hypertensive crisis † 1	1/438 (0.23%)	1	0/428 (0.00%)	0	0/440 (0.00%)	0
Phlebitis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
Venous thrombosis † 1	0/438 (0.00%)	0	0/428 (0.00%)	0	1/440 (0.23%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3%
	Benralizumab 30 mg q.4 Weeks		Benralizumab 30 mg q.8 Weeks		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	244/438 (55.71%)		232/428 (54.21%)		264/440 (60.00%)
General disorders
Pyrexia † 1	16/438 (3.65%)	20	13/428 (3.04%)	13	6/440 (1.36%)	6
Infections and infestations
Acute sinusitis † 1	6/438 (1.37%)	6	5/428 (1.17%)	6	14/440 (3.18%)	19
Bronchitis † 1	40/438 (9.13%)	51	45/428 (10.51%)	54	54/440 (12.27%)	72
Influenza † 1	24/438 (5.48%)	27	12/428 (2.80%)	17	25/440 (5.68%)	27
Nasopharyngitis † 1	90/438 (20.55%)	132	82/428 (19.16%)	131	92/440 (20.91%)	147
Pharyngitis † 1	17/438 (3.88%)	21	10/428 (2.34%)	10	8/440 (1.82%)	9
Rhinitis † 1	12/438 (2.74%)	13	18/428 (4.21%)	24	17/440 (3.86%)	22
Sinusitis † 1	23/438 (5.25%)	31	21/428 (4.91%)	30	39/440 (8.86%)	56
Upper respiratory tract infection † 1	29/438 (6.62%)	35	37/428 (8.64%)	53	42/440 (9.55%)	53
Musculoskeletal and connective tissue disorders
Arthralgia † 1	8/438 (1.83%)	10	14/428 (3.27%)	16	10/440 (2.27%)	14
Back pain † 1	17/438 (3.88%)	18	11/428 (2.57%)	11	16/440 (3.64%)	20
Nervous system disorders
Headache † 1	33/438 (7.53%)	63	34/428 (7.94%)	65	32/440 (7.27%)	57
Respiratory, thoracic and mediastinal disorders
Asthma † 1	50/438 (11.42%)	76	32/428 (7.48%)	50	52/440 (11.82%)	96
Cough † 1	10/438 (2.28%)	11	14/428 (3.27%)	18	8/440 (1.82%)	12
Rhinitis allergic † 1	21/438 (4.79%)	25	16/428 (3.74%)	19	24/440 (5.45%)	28
Vascular disorders
Hypertension † 1	12/438 (2.74%)	12	18/428 (4.21%)	23	22/440 (5.00%)	24
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.1

Limitations and Caveats

[Not Specified]

More Information

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.

≥ 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.

Results Point of Contact

• Name/Title: Mitchell Goldman, Medical Science Director
• Organization: AstraZeneca
• Phone: +1 301 398 0323
• EMail: Mitchell.Goldman@astrazeneca.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 May;39(5):2065-2084. doi: 10.1007/s12325-022-02098-1. Epub 2022 Mar 14.

Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Aug;125(2):171-176. doi: 10.1016/j.anai.2020.04.011. Epub 2020 Apr 22.

Jackson DJ, Humbert M, Hirsch I, Newbold P, Garcia Gil E. Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma. Adv Ther. 2020 Feb;37(2):718-729. doi: 10.1007/s12325-019-01191-2. Epub 2019 Dec 14.

Chipps BE, Hirsch I, Trudo F, Alacqua M, Zangrilli JG. Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Jan;124(1):79-86. doi: 10.1016/j.anai.2019.10.006. Epub 2019 Oct 15.

Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2019 May;122(5):478-485. doi: 10.1016/j.anai.2019.02.016. Epub 2019 Feb 23.

Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, Goldman M, Newbold P, Zangrilli JG. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018 Oct 18;52(4):1800936. doi: 10.1183/13993003.00936-2018. Print 2018 Oct.

DuBuske L, Newbold P, Wu Y, Trudo F. Seasonal variability of exacerbations of severe, uncontrolled eosinophilic asthma and clinical benefits of benralizumab. Allergy Asthma Proc. 2018 Sep 4;39(5):345-349. doi: 10.2500/aap.2018.39.4162. Epub 2018 Aug 4.

Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018 May;120(5):504-511.e4. doi: 10.1016/j.anai.2018.01.030. Epub 2018 Feb 1.

Ohta K, Adachi M, Tohda Y, Kamei T, Kato M, Mark Fitzgerald J, Takanuma M, Kakuno T, Imai N, Wu Y, Aurivillius M, Goldman M. Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma. Allergol Int. 2018 Apr;67(2):266-272. doi: 10.1016/j.alit.2017.10.004. Epub 2017 Nov 8.

FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkstrom V, Aurivillius M, Goldman M; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29;388(10056):2128-2141. doi: 10.1016/S0140-6736(16)31322-8. Epub 2016 Sep 5.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01914757
• Other Study ID Numbers: D3250C00018
• First Submitted: July 31, 2013
• First Posted: August 2, 2013
• Results First Submitted: September 8, 2016
• Results First Posted: January 25, 2017
• Last Update Posted: January 25, 2017