Efficacy and Safety Study of Benralizumab in patients With Uncontrolled Asthma on Medium to High Dose Inhaled Corticosteroid Plus LABA (MIRACLE)

Study identifier:D3250C00036

ClinicalTrials.gov identifier:NCT03186209

EudraCT identifier:2017-000702-38

CTIS identifier:N/A

Study Complete

Official Title

A Multicentre, Randomised, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) Added to Medium to High-dose Inhaled Corticosteroid Plus Long-acting β2 Agonist in Patients with Uncontrolled Asthma.

Medical condition

asthma

Phase

Phase 3

Healthy volunteers

Study drug

Sex

All

Actual Enrollment

695

Study type

Interventional

Age

12 Years - 75 Years

Date

Study Start Date: 07 Sept 2017

Primary Completion Date: 30 Jan 2023

Study Completion Date: 30 Jan 2023

Study design

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

Verification:

Verified 01 Mar 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Written informed consent, and assent when applicable for study participation must be obtained prior to any study related procedures being performed (local regulations are to be followed in determining the assent/consent requirements for children and parent[s]/guardian[s]) and according to international guidelines and/or applicable local guidelines.
2. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1. For those patients, who are 17 on the day of Visit 1 but will turn 18 after this day, will be considered an adolescent for the purposes of this trial.
3. History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (>250μg fluticasone propionate dry powder formulation equivalents total daily dose) and a LABA, for at least 6 months prior to Visit 1.
4. Additional maintenance asthma controller medications that are locally approved in a country for the treatment of asthma (e.g., leukotriene receptor antagonists (LTRAs), tiotropium, chromone, theophylline, oral corticosteroid), and have been used for at least 30 days prior to Visit 1 are allowed.
5. At least 2 documented asthma exacerbations in the 12 months prior to the date informed consent, and assent when available, during the treatment of medium-to-high dose ICS-LABA that required use of a systemic corticosteroid or a temporary increase from the patient’s usual maintenance dose of oral corticosteroid. For patients who are re-screened within 30 days of their screen failure date, the calculation of the 12 month period should be done from the original informed consent, and assent when applicable date.
6. Documented post-bronchodilator (post-BD) reversibility in FEV1 of >12% and >200 mL in FEV1 within 12 months prior to Visit 1. If historical documentation is not available, reversibility must be demonstrated and documented at Visit 2.
7. Fulfilment of at least 1 of the following conditions over the 7 days prior to randomization:
- >2 days with a daytime or night time symptoms score >1
- Rescue Short-acting β2 agonist (SABA) use on >2 days
- ≥1 nocturnal awakening due to asthma
8. Pre-bronchodilator (Pre-BD) FEV1 of <80% predicted (<90% predicted for patients aged 12 to 17 years) at Visit 2.
9. ACQ-6 score > = 1.5 at Visit 2.
Exclusion Criteria:
1. Known history of clinically important pulmonary disease other than asthma (e.g., active lung infection, chronic obstructive pulmonary disease (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 (e.g,. allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
2. Known history of any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 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
- Influence the findings of the studies or their interpretations
- Impede the patient’s ability to complete the entire duration of study.
3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent, and assent when applicable, is obtained or during the screening period.
4. Any clinically significant abnormal findings in physical examination, vital signs, haematology, 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.
5. Current smokers or former smokers with a smoking history of > 10 pack-years.

Location

Research Site

Guangzhou, China, 510120

Location

Research Site

Shanghai, China, 200032

Location

Research Site

Wuhan, China, 430030

Location

Research Site

Nanjing, China, 210029

Location

Research Site

Shanghai, China, 200025

Location

Research Site

Nanjing, China, 210009

Location

Research Site

Nanjing, China, 2100008

Location

Research Site

Haikou, China, 570311

Arms	Assigned Interventions
Experimental: Benralizumab Benralizumab administered subcutaneously	Biological/Vaccine: Benralizumab Benralizumab subcutaneously on study week 0 until study week 40 inclusive.
Placebo Comparator: Placebo Placebo administered subcutaneously	Biological/Vaccine: Placebo Placebo subcutaneously on study week 0 until study week 40 inclusive.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
695 participants were randomized to receive treatment in study D3250C00036 (MIRACLE) with Benralizumab or placebo. All the 695 randomized participants received treatment with study drug.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
At the first visit, ie, the enrollment visit 1, participants were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrollment, eligible participants were randomized to either placebo or Benralizumab 30 mg at a 1:1 ratio, administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks thereafter.

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Participant Flow: Overall Study

	Benralizumab 30 mg	Placebo
STARTED	348	347
Dosed	348	347
COMPLETED	331	321
NOT COMPLETED	17	26
Withdrawal by Subject	11	22
Pregnancy	1	0
Adverse Event	4	0
V18 SKIPPED DUE TO LOGISTICS REASON	1	0
PI DECIDED TO DISCONTINUE THE STUDY DUE TO THE LACK OF CRC RESOURCES	0	2
Fail to meet randomization criteria	0	1
Lost to Follow-up	0	1

Baseline Characteristics

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

Full analysis set, all participants who were randomized and received at least one investigational product (IP), Benralizumab or Placebo.

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Baseline Measures

	Benralizumab 30 mg	Placebo	Total
Number of Participants [units: Participants]	348	347	695
Race/Ethnicity, Customized [units: Participants]
Hispanic or Latino	0	0	0
Non-Hispanic or Latino	348	347	695
Asian	348	347	695
Sex: Female, Male [units: Participants]
Female	221	207	428
Male	127	140	267
Age Continuous [units: years] Mean ± Standard Deviation	51.1 ± 11.56	51.0 ± 12.56	51.1 ± 12.06
Age, Customized [units: Participants]
>=12 - <18 years	1	0	1
>=18 - <65 years	299	295	594
>=65 - <=75	48	52	100

Outcome Measures

1. Primary Outcome Measure: Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Primary
Measure Name	Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL
Measure Description	Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	236	237
Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL [units: events/patient-year] Least Squares Mean (95% Confidence Interval)	0.49 (0.33 to 0.72)	1.88 (1.35 to 2.61)

Statistical Analysis 1 for Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Other [Negative binomial]
P-Value^[4]	<0.0001
Other^[5]	0.26
95% Confidence Interval	( 0.19 to 0.36 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model with covariates: treatment group, region (China/Non-China), number of exacerbations in previous year, use of maintenance oral corticosteroids
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Multiplicity protected by hierarchy testing procedure. First in line hypothesis testing, requiring p-value <0.05.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	215	204
Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Liter] Mean (Standard Deviation)	0.333 (0.4499)	0.103 (0.4841)

Statistical Analysis 1 for Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	0.25
95% Confidence Interval	( 0.17 to 0.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline pre-bronchodilator FEV1, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Test after significant primary endpoint. Two secondary endpoints (change in FEV1 and total asthma symptom score) using Holm's procedure; smaller p-value to be <0.025, and larger p-value to be <0.05.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Daytime and nighttime symptoms are reported using a response scale ranging from 0 to 3 where 0 indicates no asthma symptoms. The total asthma symptom score is the sum of the daytime and nighttime scores and ranges from 0 to 6; a decrease in score indicates symptom improvement.
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	213	206
Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Scores on a scale] Mean (Standard Deviation)	-1.07 (1.126)	-0.80 (1.129)

Statistical Analysis 1 for Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0126
Mean Difference (Final Values)^[5]	-0.25
95% Confidence Interval	( -0.45 to -0.05 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline total asthma symptom score, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Test after significant primary endpoint. Two secondary endpoints (change in FEV1 and total asthma symptom score) using Holm's procedure; smaller p-value to be <0.025, and larger p-value to be <0.05.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Change from baseline at week 48 in total rescue medication use (number of puffs/day)
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	213	206
Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Puffs/day] Mean (Standard Deviation)	-0.85 (1.865)	-0.89 (2.213)

Statistical Analysis 1 for Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.1835
Mean Difference (Final Values)^[5]	-0.17
95% Confidence Interval	( -0.42 to 0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline total asthma rescue medication use, region, use of maintenance oral corticosteroids, visit, treatment*visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Change from baseline at week 48 in morning PEF
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	213	207
Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: L/min] Mean (Standard Deviation)	54.194 (86.3963)	12.995 (68.7947)

Statistical Analysis 1 for Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	38.66
95% Confidence Interval	( 24.24 to 53.07 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline morning PEF, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Change from baseline at week 48 in evening PEF
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	217	209
Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: L/min] Mean (Standard Deviation)	45.661 (85.4642)	7.989 (68.0632)

Statistical Analysis 1 for Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	35.85
95% Confidence Interval	( 21.52 to 50.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline evening PEF, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Change from baseline at Week 48 in proportion of night awakening due to asthma and requiring rescue medication
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	217	208
Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Proportion of nights] Mean (Standard Deviation)	-0.15 (0.220)	-0.15 (0.260)

Statistical Analysis 1 for Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.3385
Mean Difference (Final Values)^[5]	-0.01
95% Confidence Interval	( -0.03 to 0.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline proportion of nights awakening, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure 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.
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	218	212
Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Scores on a scale] Mean (Standard Deviation)	-1.22 (0.901)	-0.79 (0.962)

Statistical Analysis 1 for Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.43
95% Confidence Interval	( -0.58 to -0.28 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline ACQ-6 score, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Time to first asthma exacerbation over 48-week treatment period
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	236	237
Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Days] Median (95% Confidence Interval)	NA (NA to NA) ^[1]	227 (146 to NA) ^[1]

Statistical Analysis 1 for Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Regression, Cox
P-Value^[4]	<0.0001
Hazard Ratio (HR)^[5]	0.32
95% Confidence Interval	( 0.23 to 0.43 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	model including covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

10. Secondary Outcome Measure: Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Number and percentage of patients with at least one exacerbation over 48-week treatment period
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	236	237
Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: participants]	55	125

Statistical Analysis 1 for Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	<0.0001
Odds Ratio (OR)^[5]	0.28
95% Confidence Interval	( 0.19 to 0.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Controlling for region, number of exacerbations in the previous year (2, >=3), use of OCS
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

11. Secondary Outcome Measure: Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	The SGRQ is a 50-item PRO instrument developed to measure the HRQoL of patients with airway diseases. The questionnaire is divided into two parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition. The total score indicates the impact of disease on overall HRQoL. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible HRQoL and 0 indicates the best possible HRQoL.
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	209	200
Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Scores on a scale] Mean (Standard Deviation)	-23.24 (20.509)	-14.75 (21.838)

Statistical Analysis 1 for Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-9.19
95% Confidence Interval	( -12.79 to -5.60 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model with covariates: treatment group, baseline SGRQ total score, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

12. Secondary Outcome Measure: Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization over 48-week treatment period
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	236	237
Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: events/patient-year] Least Squares Mean (95% Confidence Interval)	0.06 (0.04 to 0.11)	0.14 (0.09 to 0.20)

Statistical Analysis 1 for Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Other [Negative binomial]
P-Value^[4]	0.0222
Other^[5]	0.46
95% Confidence Interval	( 0.24 to 0.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, use of maintenance oral corticosteroids, categorical variable of ER/UC or hospitalization exacerbations during previous year
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

13. Secondary Outcome Measure: Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Asthma specific health care resource utilization over 48-week treatment period.
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	236	237
Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: participants]
Hospitalisations	6	21
Emergency Department Visits	11	12
Unscheduled Outpatient Visits	53	99
Home Visits	1	2
Telephone Calls	35	71
Ambulance Transports	2	2
Advanced Pulmonary Function Test	4	8

No statistical analysis provided for Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

14. Secondary Outcome Measure: The pharmacokinetics (PK) of benralizumab as assessed by trough concentration [ Time Frame: week 0, week 24, week 48 ]

Measure Type	Secondary
Measure Name	The pharmacokinetics (PK) of benralizumab as assessed by trough concentration
Measure Description	PK trough concentrations at each visit
Time Frame	week 0, week 24, week 48
Safety Issue?

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.
PK analysis set; number analyzed includes participants with available value at each specified time point.

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	345	0
The pharmacokinetics (PK) of benralizumab as assessed by trough concentration [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Week 0	0 (0%)
Week 24	137.914 (432.419%)
Week 48	123.476 (395.951%)

No statistical analysis provided for The pharmacokinetics (PK) of benralizumab as assessed by trough concentration

15. Secondary Outcome Measure: The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs) [ Time Frame: Pre-treatment until end of 48-week end of treatment ]

Measure Type	Secondary
Measure Name	The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs)
Measure Description	Anti-drug antibodies (ADA) responses at baseline and post baseline.
Time Frame	Pre-treatment until end of 48-week end of treatment
Safety Issue?

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.
Safety analysis set; number analyzed includes participants with available value at each specified time point.

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	348	347
The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs) [units: participants]
ADA positive at any time, including baseline and/or post-baseline (ADA prevalence)	58	6
Treatment-emergent ADA positive, including treatment-induced and treatment-boosted ADA positive	58	2
Treatment-induced ADA positive	56	2
Treatment-boosted ADA positive	2	0
ADA positive at both baseline and at least one post-baseline assessment	2	2
ADA positive at baseline only	0	2
ADA persistently positive	40	1
ADA transiently positive	16	1
ADA positive with maximum titre > median of maximum titres	25	2
ADA positive with maximum titre <= median of maximum titres	33	4
nAb prevalence (nAb positive at any time, including baseline and/or post-baseline)	55	1
nAb incidence	55	1

No statistical analysis provided for The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs)

16. Secondary Outcome Measure: Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Secondary
Measure Name	Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
Measure Description	Percent change from baseline at Week 48 in blood eosinophil levels
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils >=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	213	199
Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL [units: Percent change] Mean (Standard Deviation)	-80.6 (34.65)	42.3 (380.86)

Statistical Analysis 1 for Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-119.31
95% Confidence Interval	( -169.78 to -68.84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	model includes treatment , baseline eosinophil count, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

17. Other Pre-specified Outcome Measure: Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [ Time Frame: From randomization through Study Week 48. ]

Measure Type	Other Pre-specified
Measure Name	Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
Measure Description	Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
Time Frame	From randomization through Study Week 48.
Safety Issue?

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.
Full analysis set, Baseline eosinophils <300/uL

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	112	110
Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [units: events/patient-year] Least Squares Mean (95% Confidence Interval)	0.72 (0.49 to 1.06)	0.87 (0.61 to 1.24)

Statistical Analysis 1 for Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

Groups^[1]	All groups
Method^[3]	Other [Negative binomial]
P-Value^[4]	0.4519
Other^[5]	0.83
95% Confidence Interval	( 0.51 to 1.35 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model with covariates: treatment group, region (China/Non-China), number of exacerbations in previous year, use of maintenance oral corticosteroids
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

18. Other Pre-specified Outcome Measure: Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Other Pre-specified
Measure Name	Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
Measure Description	Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils <300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	101	97
Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [units: Liter] Mean (Standard Deviation)	0.178 (0.4068)	0.045 (0.3626)

Statistical Analysis 1 for Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0214
Mean Difference (Final Values)^[5]	0.12
95% Confidence Interval	( 0.02 to 0.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline pre-bronchodilator FEV1, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

19. Other Pre-specified Outcome Measure: Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [ Time Frame: From randomization through Study Week 48 ]

Measure Type	Other Pre-specified
Measure Name	Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
Measure Description	Daytime and nighttime symptoms are reported using a response scale ranging from 0 to 3 where 0 indicates no asthma symptoms. The total asthma symptom score is the sum of the daytime and nighttime scores and ranges from 0 to 6; a decrease in score indicates symptom improvement.
Time Frame	From randomization through Study Week 48
Safety Issue?

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.
Full analysis set, Baseline eosinophils <300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Measured Values

	Benralizumab 30 mg	Placebo
Number of Participants Analyzed [units:participants]	101	94
Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL [units: Scores on a scale] Mean (Standard Deviation)	-0.97 (1.260)	-0.75 (1.105)

Statistical Analysis 1 for Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.1589
Mean Difference (Final Values)^[5]	-0.21
95% Confidence Interval	( -0.51 to 0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes Treatment, baseline total asthma symptom score, region, use of maintenance oral corticosteroids, visit, and treatment by visit
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-value. Not multiplicity protected by testing procedure.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	From initial dose of the study treatment to the end of study, i.e., up to 56 weeks of follow-up.
Additional Description	All treated participants from the first dose to the end of study. Total of 695 participants with 348 participants treated with Benralizumab administered every 4 weeks for the first 3 doses and then every 8 weeks and 347 were under placebo treatment.

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Serious Adverse Events

Benralizumab 30 mg

Placebo

Total, serious adverse events

# participants affected / at risk

44/348 (12.64%)

63/347 (18.16%)

Cardiac disorders

Arteriosclerosis coronary artery¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Reflux gastritis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Hepatobiliary disorders

Cholecystitis¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Hepatobiliary disorders

Hepatic mass¹,^†

# participants affected / at risk

1/348 (0.29%)

1/347 (0.29%)

# events

Immune system disorders

Food allergy¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Asymptomatic COVID-19¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Bronchopulmonary aspergillosis¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Infections and infestations

Bronchopulmonary aspergillosis allergic¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Chronic sinusitis¹,^†

# participants affected / at risk

2/348 (0.57%)

0/347 (0.00%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

0/348 (0.00%)

2/347 (0.58%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Infections and infestations

Otitis media¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Pelvic infection¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

3/348 (0.86%)

6/347 (1.73%)

# events

Infections and infestations

Pneumonia bacterial¹,^†

# participants affected / at risk

3/348 (0.86%)

3/347 (0.86%)

# events

Infections and infestations

Pneumonia pneumococcal¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Pulmonary tuberculosis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Injury, poisoning and procedural complications

Femoral neck fracture¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Injury, poisoning and procedural complications

Ligament sprain¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Injury, poisoning and procedural complications

Multiple fractures¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Injury, poisoning and procedural complications

Patella fracture¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Injury, poisoning and procedural complications

Road traffic accident¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Fibromyalgia¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹,^†

# participants affected / at risk

1/348 (0.29%)

2/347 (0.58%)

# events

Musculoskeletal and connective tissue disorders

Osteoarthropathy¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Musculoskeletal and connective tissue disorders

Osteoporosis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Periarthritis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Rotator cuff syndrome¹,^†

# participants affected / at risk

2/348 (0.57%)

0/347 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Tendonitis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

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

Adenolymphoma¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

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

Intraductal papilloma of breast¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

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

Ovarian adenoma¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

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

Ovarian germ cell teratoma benign¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

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

Uterine leiomyoma¹,^†

# participants affected / at risk

1/348 (0.29%)

2/347 (0.58%)

# events

Nervous system disorders

Cerebral infarction¹,^†

# participants affected / at risk

1/348 (0.29%)

1/347 (0.29%)

# events

Nervous system disorders

Cerebral ischaemia¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Renal and urinary disorders

Renal mass¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Reproductive system and breast disorders

Uterine polyp¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Reproductive system and breast disorders

Uterine prolapse¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

12/348 (3.45%)

33/347 (9.51%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchiectasis¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Respiratory, thoracic and mediastinal disorders

Lung opacity¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal polyps¹,^†

# participants affected / at risk

3/348 (0.86%)

1/347 (0.29%)

# events

Respiratory, thoracic and mediastinal disorders

Sinus polyp¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Vocal cord polyp¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Skin and subcutaneous tissue disorders

Urticaria¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Vascular disorders

Arteriosclerosis¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Vascular disorders

Neurogenic shock¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Eye disorders

Cataract¹,^†

# participants affected / at risk

1/348 (0.29%)

3/347 (0.86%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Chronic gastritis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Duodenitis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Enteritis¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Gastritis erosive¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Haemorrhoids¹,^†

# participants affected / at risk

0/348 (0.00%)

1/347 (0.29%)

# events

Gastrointestinal disorders

Irritable bowel syndrome¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

Gastrointestinal disorders

Large intestine polyp¹,^†

# participants affected / at risk

1/348 (0.29%)

0/347 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.1

Other Adverse Events

Time Frame	From initial dose of the study treatment to the end of study, i.e., up to 56 weeks of follow-up.
Additional Description	All treated participants from the first dose to the end of study. Total of 695 participants with 348 participants treated with Benralizumab administered every 4 weeks for the first 3 doses and then every 8 weeks and 347 were under placebo treatment.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Benralizumab 30 mg	Benralizumab administered subcutaneously
Placebo	Placebo administered subcutaneously

Other Adverse Events

Benralizumab 30 mg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

194/348 (55.75%)

194/347 (55.91%)

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

18/348 (5.17%)

9/347 (2.59%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

11/348 (3.16%)

27/347 (7.78%)

# events

Infections and infestations

COVID-19¹,^†

# participants affected / at risk

11/348 (3.16%)

6/347 (1.73%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

28/348 (8.05%)

33/347 (9.51%)

# events

Infections and infestations

Otitis media¹,^†

# participants affected / at risk

11/348 (3.16%)

8/347 (2.31%)

# events

Infections and infestations

Pharyngitis¹,^†

# participants affected / at risk

13/348 (3.74%)

13/347 (3.75%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

9/348 (2.59%)

16/347 (4.61%)

# events

Infections and infestations

Rhinitis¹,^†

# participants affected / at risk

13/348 (3.74%)

6/347 (1.73%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

120/348 (34.48%)

120/347 (34.58%)

# events

200

230

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

9/348 (2.59%)

12/347 (3.46%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

11/348 (3.16%)

8/347 (2.31%)

# events

Respiratory, thoracic and mediastinal disorders

Rhinitis allergic¹,^†

# participants affected / at risk

22/348 (6.32%)

15/347 (4.32%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

7/348 (2.01%)

13/347 (3.75%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.1

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: The Institution and/or the Principal Investigator shall not include in or shall remove from any proposed publication any Confidential Information, errors or inaccuracies; and shall withhold publication, submission for publication or presentation for a period of ninety (90) days from the date on which the Company receives the material to allow the Company to take such measures as the Company considers necessary to preserve its proprietary rights and/or protect its Confidential Information.

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
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Results Point of Contact

Name/Title:	Global Clinical Head
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Redacted CSP
Download
Redacted SAP
Download
Redacted CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Redacted CSP

Redacted SAP

Redacted CSR Synopsis

Trial Results Summaries