Benralizumab efficacy in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) with exacerbation history - GALATHEA

Study identifier:D3251C00003

ClinicalTrials.gov identifier:NCT02138916

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Randomised, double-blind, 56 week placebo-controlled, parallel group, multicentre, phase 3 study to evaluate the efficacy and safety of 2 doses of benralizumab in patients with moderate to very severe COPD with a history of exacerbations

Medical condition

Moderate to very severe Chronic Obstructive Pulmonary Disease

Phase

Phase 3

Healthy volunteers

Study drug

Benralizumab Arm A, Benralizumab Arm B, Placebo

Sex

All

Actual Enrollment

1656

Study type

Interventional

Age

40 Years - 85 Years

Date

Study Start Date: 13 Jun 2014

Primary Completion Date: 10 Apr 2018

Study Completion Date: 10 Apr 2018

Study design

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

Verification:

Verified 01 Jun 2019 by AstraZeneca

Collaborators

MedImmune

Inclusion and exclusion criteria

Inclusion Criteria

1.Informed consent. 2.Subjects 40-85 y.o. 3.Moderate to very severe COPD with Post Bronchodilator (BD) FEV1>20% and ≤65%. 4.≥2 moderate or ≥1 severe COPD exacerbation(s) required treatment or hospitalization within 2-52 weeks prior to Visit1. 5. Modified Medical Research Council (mMRC) score ≥1 at Visit 1. 6.Treatment with double or triple therapy throughout the year prior to Visit 1, constant 2 weeks prior to Visit 1. 7.Tobacco history of ≥10 pack-years. 8.Women of childbearing potential must use a highly effective form of birth control from Visit 1 until 16 weeks after their last dose, and negative serum pregnancy test result at Visit 1. 9.Male subjects who are sexually active must be surgically sterile one year prior to Visit 1 or use an adequate method of contraception from the first Investigational Product (IP) dose until 16 weeks after their last dose. 10.Compliance with maintenance therapy during run-in ≥70%. 11. Blood eosinophils due to subject’s stratification and cap for blood eosinophil levels.When any eosinophil cohort is full, subjects in the completed cohort will not be randomised and will be withdrawn from the study.

Exclusion Criteria

1. Clinically important pulmonary disease other than COPD or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
2. Any disorder or major physical impairment that is not stable by Investigator opinion and/or could affect: - subject safety−study findings or their interpretation or subject’s ability to complete the entire study duration.
3. Unstable ischemic heart disease, arrhythmia, cardiomyopathy, or other relevant cardiovascular disorder that in Investigator’s judgment may put the patient at risk or negatively affect the study outcome.
4. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 2 weeks prior to Visit1 or during the enrolment and run-in period.
5. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 2 weeks prior to Visit1or during the enrolment and run-in period.
6. Pneumonia within 8 weeks prior to Visit1 or during the enrolment and run-in period.
7. Pregnant, breastfeeding, or lactating women.
8. Risk factors for pneumonia
9. History of anaphylaxis to any other biologic therapy.
10. Long term oxygen therapy with signs and/or symptoms of cor pulmonale, right ventricular failure.
11. Use of immunosuppressive medication within 2 weeks prior to Visit1 and/or during the enrolment and run-in period.
12. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to Visit 1.
13. Evidence of active tuberculosis (TB) without an appropriate course of treatment.
14. Lung volume reduction surgery within the 6 months prior to Visit 1. History of partial or total lung resection (single lobe or segmentectomy is acceptable).
15. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines or other accepted guidelines.
16. Previous treatment with benralizumab.
17. Helminth parasitic infection diagnosed within 24 weeks prior to Visit 1.

124

Location

Research Site

Frankfurt, Germany, 60596

Location

Research Site

Neu-Isenburg, Germany, 63263

Location

Research Site

Berlin, Germany, 13187

Location

Research Site

Marburg, Germany, 35043

Location

Research Site

Bamberg, Germany, 96049

Location

Research Site

Frankfurt am Main, Germany, 60596

Location

Research Site

Hamburg, Germany, 20354

Location

Research Site

Linz, Austria, 4020

Arms	Assigned Interventions
Experimental: Benralizumab Arm A Benralizumab administered subcutaneously	Drug: Benralizumab Arm A Benralizumab subcutaneously on study week 0 until study week 48 inclusive
Experimental: Benralizumab Arm B Benralizumab administered subcutaneously	Drug: Benralizumab Arm B Benralizumab subcutaneously on study week 0 until study week 48 inclusive
Placebo Comparator: Placebo Placebo administered subcutaneously	Drug: Placebo Placebo subcutaneously on study week 0 until study week 48 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
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1656 patients randomized to Benralizumab 30 mg, Benralizumab 100 mg, or Placebo. All randomized patients were treated. 554 (33.5%) were randomized to Benralizumab 30 mg, 552 (33.3%) were randomized to Benralizumab 100 mg, and 550 (33.2%) were randomized to Placebo.

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Participant Flow: Overall Study

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
STARTED	554	552	550
COMPLETED	497	492	491
NOT COMPLETED	57	60	59
eg., meds change, lack of efficacy, etc.	6	9	7
Death	14	11	12
Withdrawal by Subject	27	31	32
Study specific withdrawal criteria	0	0	1
incorrect enrolment	1	1	0
Severe non-compliance	1	2	1
Lost to Follow-up	4	2	3
Adverse Event	4	4	3

Baseline Characteristics

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

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Baseline Measures

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo	Total
Number of Participants [units: Participants]	554	552	550	1656
Age Continuous [units: Year] Mean ± Standard Deviation	65.9 ± 7.77	65.3 ± 8.05	65.2 ± 8.22	65.5 ± 8.01
Sex: Female, Male [units: Participants]
Female	172	180	175	527
Male	382	372	375	1129
Race/Ethnicity, Customized [units: Participants]
White	496	493	488	1477
Black or African American	4	11	10	25
Asian	48	46	46	140
Other	6	2	6	14

Outcome Measures

1. Primary Outcome Measure: Annual COPD exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL [ Time Frame: From first IP to week 56 ]

Measure Type	Primary
Measure Name	Annual COPD exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
Measure Description	A COPD exacerbation is defined by symptomatic worsening of COPD requiring: • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or • Use of antibiotics; and/or • An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time Frame	From first IP to week 56
Safety Issue?	No

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No

2. Secondary Outcome Measure: Annual COPD exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS<220/uL [ Time Frame: From first IP to week 56 ]

Measure Type	Secondary
Measure Name	Annual COPD exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS<220/uL
Measure Description	A COPD exacerbation is defined by symptomatic worsening of COPD requiring: • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or • Use of antibiotics; and/or • An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time Frame	From first IP to week 56
Safety Issue?	No

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No

3. Secondary Outcome Measure: Mean change from baseline to Week 56 in pre-bronchodilator FEV1 (L) value for patients with baseline EOS>=220/uL [ Time Frame: First IP up to end of treatment Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline to Week 56 in pre-bronchodilator FEV1 (L) value for patients with baseline EOS>=220/uL
Measure Description	Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment.
Time Frame	First IP up to end of treatment Week 56
Safety Issue?	No

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No

4. Secondary Outcome Measure: Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL
Measure Description	SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status.
Time Frame	First IP up to Week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	338	331	317
Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL [units: Percentage] Mean (Standard Deviation)	-5.025 (14.677)	-6.723 (15.723)	-3.913 (15.039)

Statistical Analysis 1 for Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.2906
Mean Difference (Final Values)^[5]	-1.011
95% Confidence Interval	( -2.887 to 0.865 )

[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 group, baseline SGRQ score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0264
Mean Difference (Final Values)^[5]	-2.136
95% Confidence Interval	( -4.020 to -0.251 )

[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 group, baseline SGRQ score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL
Measure Description	CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status.
Time Frame	First IP up to Week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	338	335	319
Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL [units: Score on a scale] Mean (Standard Deviation)	-1.50 (6.89)	-2.43 (6.34)	-1.22 (6.53)

Statistical Analysis 1 for Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.6782
Mean Difference (Final Values)^[5]	-0.19
95% Confidence Interval	( -1.08 to 0.70 )

[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 group, baseline CAT total score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0753
Mean Difference (Final Values)^[5]	-0.81
95% Confidence Interval	( -1.70 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 group, baseline CAT total score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL
Measure Description	The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.
Time Frame	First IP up to Week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	324	328	295
Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL [units: Score on a scale] Mean (Standard Deviation)	-1.085 (5.273)	-1.354 (5.599)	-0.504 (5.674)

Statistical Analysis 1 for Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0889
Mean Difference (Final Values)^[5]	-0.585
95% Confidence Interval	( -1.260 to 0.089 )

[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 group, baseline total score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0413
Mean Difference (Final Values)^[5]	-0.703
95% Confidence Interval	( -1.378 to -0.028 )

[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 group, baseline total score, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL
Measure Description	The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.
Time Frame	First IP up to Week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	321	322	291
Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL [units: Puffs/day] Mean (Standard Deviation)	-0.05 (3.21)	-0.27 (2.71)	0.29 (3.03)

Statistical Analysis 1 for Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0728
Mean Difference (Final Values)^[5]	-0.348
95% Confidence Interval	( -0.728 to 0.032 )

[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 group, baseline rescue med. use, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0121
Mean Difference (Final Values)^[5]	-0.487
95% Confidence Interval	( -0.868 to -0.107 )

[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 group, baseline rescue med. use, EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]

Measure Type	Secondary
Measure Name	Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL
Measure Description	Change from baseline to week 56 in proportion of nights awakenings due to respiratory symptoms.
Time Frame	First IP up to Week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	325	323	297
Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL [units: Proportion of nights] Mean (Standard Deviation)	-0.088 (0.310)	-0085 (0.283)	-0.049 (0.307)

Statistical Analysis 1 for Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0235
Mean Difference (Final Values)^[5]	-0.041
95% Confidence Interval	( -0.077 to -0.006 )

[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 group, baseline prop. of nights awakens., EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0158
Mean Difference (Final Values)^[5]	-0.044
95% Confidence Interval	( -0.080 to -0.008 )

[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 group, baseline prop. of nights awakens., EOS cohort, region, background therapy, visit, and treatment by visit interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: Number of participants by number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Number of participants by number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL
Measure Description	The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Exacerbation event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an exacerbation event has occurred.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	378	358
Number of participants by number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL [units: Participants]
0	180	184	179
1	101	103	99
2	42	49	34
3	25	14	15
4	17	13	14
5	5	6	5
6	4	4	2
7	6	1	5
8	1	1	4
9	1	2	1
10	0	1	0

No statistical analysis provided for Number of participants by number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL

10. Secondary Outcome Measure: Severity of EXACT-PRO for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Severity of EXACT-PRO for patients with baseline EOS>=220/uL
Measure Description	The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Severity for the study is the highest score of EXACT-PRO.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	202	194	179
Severity of EXACT-PRO for patients with baseline EOS>=220/uL [units: Score on a scale] Mean (Standard Deviation)	51.5 (11.30)	50.8 (10.70)	52.0 (11.20)

No statistical analysis provided for Severity of EXACT-PRO for patients with baseline EOS>=220/uL

11. Secondary Outcome Measure: Duration of EXACT-PRO for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Duration of EXACT-PRO for patients with baseline EOS>=220/uL
Measure Description	The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery. That is, duration of the exacerbation is the time elapse between onset and recovery of the event.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	202	194	179
Duration of EXACT-PRO for patients with baseline EOS>=220/uL [units: Days] Mean (Standard Deviation)	82.2 (95.80)	88.3 (105.30)	101.7 (113.70)

No statistical analysis provided for Duration of EXACT-PRO for patients with baseline EOS>=220/uL

12. Secondary Outcome Measure: Annual EXACT-PRO exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Annual EXACT-PRO exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
Measure Description	The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Annual EXACT-PRO exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	378	358
Annual EXACT-PRO exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL [units: Exacerbations per year] Least Squares Mean (95% Confidence Interval)	1.14 (0.98 to 1.31)	1.02 (0.88 to 1.19)	1.04 (0.90 to 1.21)

Statistical Analysis 1 for Annual EXACT-PRO exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Other [Negative binomial]
P-Value^[4]	0.4080
Other^[5]	1.09
95% Confidence Interval	( 0.89 to 1.34 )

[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 group, EOS cohort, region, background therapy, number of exacerbations in the 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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Annual EXACT-PRO exacerbation rate over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Other [Negative binomial]
P-Value^[4]	0.8688
Other^[5]	0.98
95% Confidence Interval	( 0.80 to 1.21 )

[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 group, EOS cohort, region, background therapy, number of exacerbations in the 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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

13. Secondary Outcome Measure: Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL
Measure Description	A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	379	359
Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL [units: Participants]	204	203	198

Statistical Analysis 1 for Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.4850
Odds Ratio (OR)^[5]	0.90
95% Confidence Interval	( 0.66 to 1.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Proportion of participants with >=1 COPD exacerbation.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	CMH test controlling for EOS cohort, region, and background therapy.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.4489
Odds Ratio (OR)^[5]	0.89
95% Confidence Interval	( 0.65 to 1.21 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Proportion of participants with >=1 COPD exacerbation.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	CMH test controlling for EOS cohort, region, and background therapy.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

14. Secondary Outcome Measure: Time to first COPD exacerbation [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Time to first COPD exacerbation
Measure Description	Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	379	359
Time to first COPD exacerbation [units: Days] Median (95% Confidence Interval)	333 (273 to 400)	329 (262 to 396)	337 (261 to 390)

No statistical analysis provided for Time to first COPD exacerbation

15. Secondary Outcome Measure: Annual COPD exacerbation rate associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Annual COPD exacerbation rate associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
Measure Description	Annual COPD exacerbations rate that result in ER or hospitalization is calculated by number of exacerbations resulting ER or hospitalization divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	379	359
Annual COPD exacerbation rate associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL [units: Exacerbations per year] Least Squares Mean (95% Confidence Interval)	0.27 (0.20 to 0.35)	0.15 (0.11 to 0.20)	0.25 (0.19 to 0.33)

Statistical Analysis 1 for Annual COPD exacerbation rate associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 30 mg, Placebo
Method^[3]	Other [Negative binomial]
P-Value^[4]	0.7733
Other^[5]	1.06
95% Confidence Interval	( 0.73 to 1.53 )

[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 group, EOS cohort, region, background therapy, previous year exacerbations associated with hospitalization (Y/N).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Annual COPD exacerbation rate associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

Groups^[1]	Benralizumab 100 mg, Placebo
Method^[3]	Other [Nagative binomial]
P-Value^[4]	0.0114
Other^[5]	0.58
95% Confidence Interval	( 0.39 to 0.89 )

[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 group, EOS cohort, region, background therapy, previous year exacerbations associated with hospitalization (Y/N).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

16. Secondary Outcome Measure: Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]

Measure Type	Secondary
Measure Name	Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL
Measure Description	Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports.
Time Frame	Immediately following first IP up to week 56
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set, baseline EOS>=220/uL

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	382	379	359
Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL [units: Participants]
Hospitalisations	60	38	50
Emergency Department Visits	36	35	43
Unscheduled Outpatient Visits	219	236	202
Home Visits	18	22	18
Telephone calls	110	111	104
Ambulance transports	16	12	20

No statistical analysis provided for Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL

17. Secondary Outcome Measure: Duration of study treatment administration [ Time Frame: From first dose date to last dose date, 48 weeks per protocol. ]

Measure Type	Secondary
Measure Name	Duration of study treatment administration
Measure Description	Duration of study treatment is calculated from first dose date to last dose date + 1 day.
Time Frame	From first dose date to last dose date, 48 weeks per protocol.
Safety Issue?	No

Population Description

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

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	554	552	550
Duration of study treatment administration [units: Days] Mean (Standard Deviation)	302.4 (85.73)	304.0 (82.40)	302.5 (88.47)

No statistical analysis provided for Duration of study treatment administration

18. Secondary Outcome Measure: Serum concentration of Benralizumab [ Time Frame: Pre-first dose and pre-dose at end of treatment (week 56) ]

Measure Type	Secondary
Measure Name	Serum concentration of Benralizumab
Measure Description	PK serum samples were collected pre-dose at each visit.
Time Frame	Pre-first dose and pre-dose at end of treatment (week 56)
Safety Issue?	No

Population Description

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

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg
Number of Participants Analyzed [units:participants]	553	550
Serum concentration of Benralizumab [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Baseline	NA (NA%)^[1]	NA (NA%)^[1]
Week 56	219.45 (233.21%)	699.89 (243.20%)

No statistical analysis provided for Serum concentration of Benralizumab

19. Secondary Outcome Measure: Immunogenicity of Benralizumab [ Time Frame: Pre-treatment until end of follow-up, week 60 per protocol. ]

Measure Type	Secondary
Measure Name	Immunogenicity of Benralizumab
Measure Description	Antidrug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented
Time Frame	Pre-treatment until end of follow-up, week 60 per protocol.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
safety analysis set. For each parameter, the number of subjects at risk is to be analyzed.

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Measured Values

	Benralizumab 30 mg	Benralizumab 100 mg	Placebo
Number of Participants Analyzed [units:participants]	554	552	550
Immunogenicity of Benralizumab [units: Participants]
ADA prevalence	53	64	39
ADA incidence	44	47	24
Both base/post-baseline positive	5	7	17
Only post baseline positive	43	46	20
Only baseline positive	5	11	2
ADA persistently positive	28	34	14
ADA transiently positive	15	12	6
nAb prevalence	43	43	25
nAb incidence	41	37	18

No statistical analysis provided for Immunogenicity of Benralizumab

Serious Adverse Events

Time Frame	From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Additional Description	No text entered.

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Serious Adverse Events

Benralizumab 30 mg

Benralizumab 100 mg

Placebo

Total, serious adverse events

# participants affected / at risk

151/554 (27.26%)

177/552 (32.07%)

176/550 (32.00%)

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Blood and lymphatic system disorders

Hypochromic anaemia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Blood and lymphatic system disorders

Iron deficiency anaemia¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Cardiac disorders

Acute coronary syndrome¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

2/554 (0.36%)

1/552 (0.18%)

4/550 (0.73%)

# events

Cardiac disorders

Acute right ventricular failure¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/554 (0.18%)

3/552 (0.54%)

0/550 (0.00%)

# events

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

2/554 (0.36%)

2/552 (0.36%)

2/550 (0.36%)

# events

Cardiac disorders

Aortic valve disease¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Cardiac disorders

Aortic valve stenosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

4/554 (0.72%)

8/552 (1.45%)

2/550 (0.36%)

# events

Cardiac disorders

Atrial flutter¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

2/550 (0.36%)

# events

Cardiac disorders

Atrioventricular block complete¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Cardiac disorders

Cardiac arrest¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

3/554 (0.54%)

2/552 (0.36%)

1/550 (0.18%)

# events

Cardiac disorders

Cardiac failure acute¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

2/554 (0.36%)

2/552 (0.36%)

1/550 (0.18%)

# events

Cardiac disorders

Cardiomyopathy¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Cardiac disorders

Cor pulmonale chronic¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

0/550 (0.00%)

# events

Cardiac disorders

Coronary artery insufficiency¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Cardiac disorders

Coronary artery occlusion¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Cardiac disorders

Coronary artery stenosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

3/550 (0.55%)

# events

Cardiac disorders

Left ventricular failure¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

4/554 (0.72%)

3/552 (0.54%)

1/550 (0.18%)

# events

Cardiac disorders

Myocarditis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Cardiac disorders

Supraventricular tachycardia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Congenital, familial and genetic disorders

Exomphalos¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Abdominal wall haematoma¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Ascites¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Colitis¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

2/554 (0.36%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Diverticulum¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Enterocolitis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Gastric polyps¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Gastritis¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

2/550 (0.36%)

# events

Gastrointestinal disorders

Gastrointestinal necrosis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Haematochezia¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Haemorrhoids¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Ileus¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Inguinal hernia¹,^†

# participants affected / at risk

0/554 (0.00%)

3/552 (0.54%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Intestinal obstruction¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Intestinal perforation¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Intestinal polyp¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Irritable bowel syndrome¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Large intestine perforation¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Large intestine polyp¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

2/550 (0.36%)

# events

Gastrointestinal disorders

Mallory-Weiss syndrome¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Melaena¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Oesophageal spasm¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Pancreatitis¹,^†

# participants affected / at risk

1/554 (0.18%)

2/552 (0.36%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Pancreatitis acute¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Pancreatitis chronic¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Peritoneal haemorrhage¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

2/550 (0.36%)

# events

Gastrointestinal disorders

Salivary gland calculus¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Umbilical hernia¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Gastrointestinal disorders

Upper gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

General disorders and administration site conditions

Chest discomfort¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

General disorders and administration site conditions

Death¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

1/550 (0.18%)

# events

General disorders and administration site conditions

Multiple organ dysfunction syndrome¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

General disorders and administration site conditions

Non-cardiac chest pain¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

General disorders and administration site conditions

Sudden cardiac death¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

General disorders and administration site conditions

Systemic inflammatory response syndrome¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Hepatobiliary disorders

Cholangitis acute¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Hepatobiliary disorders

Cholecystitis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

2/554 (0.36%)

0/552 (0.00%)

1/550 (0.18%)

# events

Immune system disorders

Anaphylactic shock¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Anal abscess¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Arthritis bacterial¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Atypical mycobacterial infection¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Atypical mycobacterial lower respiratory tract infection¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

1/554 (0.18%)

3/552 (0.54%)

3/550 (0.55%)

# events

Infections and infestations

Bronchopulmonary aspergillosis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Cellulitis pharyngeal¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Cystitis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Disseminated tuberculosis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Diverticulitis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Infectious pleural effusion¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Periorbital cellulitis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Infections and infestations

Peritonsillar abscess¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

22/554 (3.97%)

18/552 (3.26%)

16/550 (2.91%)

# events

Infections and infestations

Pneumonia bacterial¹,^†

# participants affected / at risk

5/554 (0.90%)

8/552 (1.45%)

10/550 (1.82%)

# events

Infections and infestations

Pneumonia haemophilus¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Pneumonia klebsiella¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Pneumonia moraxella¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Pneumonia necrotising¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Pneumonia pneumococcal¹,^†

# participants affected / at risk

2/554 (0.36%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Pneumonia pseudomonal¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Pneumonia streptococcal¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Pneumonia viral¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Infections and infestations

Pulmonary sepsis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Infections and infestations

Pulmonary tuberculosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Infections and infestations

Respiratory syncytial virus infection¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Rhinovirus infection¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Sepsis¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

Infections and infestations

Septic shock¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

0/550 (0.00%)

# events

Infections and infestations

Staphylococcal infection¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

2/554 (0.36%)

2/552 (0.36%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Airway burns¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Arterial bypass occlusion¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Asbestosis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Chest injury¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Dural tear¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Facial bones fracture¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Femoral neck fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Foot fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Fractured coccyx¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Hip fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Joint dislocation¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Lower limb fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Patella fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Skin flap necrosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Spinal compression fracture¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Subarachnoid haemorrhage¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Subdural haematoma¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Tendon rupture¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Thoracic vertebral fracture¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Traumatic haematoma¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Upper limb fracture¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Vascular bypass dysfunction¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Vascular graft occlusion¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Vascular procedure complication¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Injury, poisoning and procedural complications

Wound¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Injury, poisoning and procedural complications

Wound dehiscence¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Investigations

Electrocardiogram ST-T change¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Metabolism and nutrition disorders

Diabetes mellitus¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Metabolism and nutrition disorders

Hyperglycaemia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Musculoskeletal and connective tissue disorders

Arthritis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Gouty arthritis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Intervertebral disc degeneration¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

1/550 (0.18%)

# events

Musculoskeletal and connective tissue disorders

Lumbar spinal stenosis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Musculoskeletal and connective tissue disorders

Osteonecrosis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Musculoskeletal and connective tissue disorders

Spinal osteoarthritis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

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

Adenocarcinoma gastric¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Adenocarcinoma of colon¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

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

Basal cell carcinoma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Benign lung neoplasm¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

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

Bladder cancer¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Colon neoplasm¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

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

Diffuse large B-cell lymphoma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Glioblastoma multiforme¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

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

Haemangioma of skin¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Laryngeal squamous cell carcinoma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Lung adenocarcinoma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

2/550 (0.36%)

# events

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

Lung neoplasm malignant¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

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

Meningioma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Non-small cell lung cancer¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Non-small cell lung cancer metastatic¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

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

Non-small cell lung cancer stage IIIB¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Pancreatic carcinoma¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

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

Plasma cell myeloma¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

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

Prostate cancer¹,^†

# participants affected / at risk

2/554 (0.36%)

1/552 (0.18%)

2/550 (0.36%)

# events

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

Prostate cancer stage II¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Renal neoplasm¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

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

Sarcoma¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Small cell lung cancer¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

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

Small cell lung cancer metastatic¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

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

Squamous cell carcinoma of skin¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

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

Tonsil cancer¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

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

Transitional cell carcinoma¹,^†

# participants affected / at risk

2/554 (0.36%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Carotid artery stenosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Nervous system disorders

Cerebral infarction¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Cerebral ischaemia¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

2/554 (0.36%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Nervous system disorders

Facial paralysis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Generalised tonic-clonic seizure¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Hyperaesthesia¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Hypoxic-ischaemic encephalopathy¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Lumbar radiculopathy¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Metabolic encephalopathy¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Monoparesis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Neuropathy peripheral¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Polyneuropathy¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Radicular syndrome¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Radiculopathy¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Sciatica¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Seizure¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Sinus headache¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Nervous system disorders

Stupor¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Thrombotic stroke¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

Psychiatric disorders

Anxiety¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Psychiatric disorders

Anxiety disorder¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Psychiatric disorders

Mental status changes¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Renal and urinary disorders

Acute kidney injury¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Reproductive system and breast disorders

Benign prostatic hyperplasia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

1/550 (0.18%)

# events

Reproductive system and breast disorders

Endometriosis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Reproductive system and breast disorders

Prostatitis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

2/550 (0.36%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchiectasis¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchitis chronic¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

1/550 (0.18%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

97/554 (17.51%)

78/552 (14.13%)

100/550 (18.18%)

# events

145

101

142

Respiratory, thoracic and mediastinal disorders

Chronic respiratory failure¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Respiratory, thoracic and mediastinal disorders

Hypercapnia¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Respiratory, thoracic and mediastinal disorders

Hypoxia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Lung consolidation¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pickwickian syndrome¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumonia aspiration¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

2/554 (0.36%)

1/552 (0.18%)

5/550 (0.91%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumothorax spontaneous¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

4/550 (0.73%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary fibrosis¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary mass¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

3/550 (0.55%)

# events

Respiratory, thoracic and mediastinal disorders

Sleep apnoea syndrome¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Skin and subcutaneous tissue disorders

Dermatomyositis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Skin and subcutaneous tissue disorders

Erythema nodosum¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Skin and subcutaneous tissue disorders

Psoriasis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Skin and subcutaneous tissue disorders

Skin laxity¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

Vascular disorders

Arterial haemorrhage¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

1/550 (0.18%)

# events

Vascular disorders

Deep vein thrombosis¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

3/550 (0.55%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

1/550 (0.18%)

# events

Vascular disorders

Hypertensive crisis¹,^†

# participants affected / at risk

1/554 (0.18%)

1/552 (0.18%)

0/550 (0.00%)

# events

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

0/554 (0.00%)

2/552 (0.36%)

0/550 (0.00%)

# events

Vascular disorders

Peripheral arterial occlusive disease¹,^†

# participants affected / at risk

0/554 (0.00%)

0/552 (0.00%)

2/550 (0.36%)

# events

Vascular disorders

Peripheral ischaemia¹,^†

# participants affected / at risk

0/554 (0.00%)

1/552 (0.18%)

0/550 (0.00%)

# events

Vascular disorders

Peripheral venous disease¹,^†

# participants affected / at risk

1/554 (0.18%)

0/552 (0.00%)

0/550 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 20.0

Other Adverse Events

Time Frame	From the time the patient signed informed consent through the treatment period up to the follow-up visit (week 60).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Benralizumab 30 mg	Every 8 weeks administered subcutaneously
Benralizumab 100 mg	Every 8 weeks administered subcutaneously
Placebo	Every 8 weeks administered subcutaneously

Other Adverse Events

Benralizumab 30 mg

Benralizumab 100 mg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

293/554 (52.89%)

318/552 (57.61%)

282/550 (51.27%)

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

17/554 (3.07%)

19/552 (3.44%)

15/550 (2.73%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

17/554 (3.07%)

15/552 (2.72%)

6/550 (1.09%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

13/554 (2.35%)

18/552 (3.26%)

13/550 (2.36%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

11/554 (1.99%)

26/552 (4.71%)

11/550 (2.00%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

59/554 (10.65%)

84/552 (15.22%)

80/550 (14.55%)

# events

113

121

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

50/554 (9.03%)

32/552 (5.80%)

29/550 (5.27%)

# events

Infections and infestations

Oral candidiasis¹,^†

# participants affected / at risk

17/554 (3.07%)

13/552 (2.36%)

15/550 (2.73%)

# events

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

10/554 (1.81%)

11/552 (1.99%)

18/550 (3.27%)

# events

Infections and infestations

Respiratory tract infection viral¹,^†

# participants affected / at risk

15/554 (2.71%)

12/552 (2.17%)

19/550 (3.45%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

13/554 (2.35%)

17/552 (3.08%)

20/550 (3.64%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

69/554 (12.45%)

74/552 (13.41%)

65/550 (11.82%)

# events

104

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

23/554 (4.15%)

22/552 (3.99%)

15/550 (2.73%)

# events

Infections and infestations

Viral upper respiratory tract infection¹,^†

# participants affected / at risk

83/554 (14.98%)

95/552 (17.21%)

66/550 (12.00%)

# events

126

134

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

21/554 (3.79%)

25/552 (4.53%)

19/550 (3.45%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

21/554 (3.79%)

26/552 (4.71%)

20/550 (3.64%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

16/554 (2.89%)

14/552 (2.54%)

21/550 (3.82%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

24/554 (4.33%)

17/552 (3.08%)

23/550 (4.18%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

14/554 (2.53%)

18/552 (3.26%)

13/550 (2.36%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

19/554 (3.43%)

19/552 (3.44%)

18/550 (3.27%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 20.0

Certain Agreements

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

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

The agreement is:

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

Limitations and Caveats

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

Results Point of Contact

Name/Title:	Ulbaldo Martin
Organization:	AstraZeneca
Phone	1.301.398.0163
E-mail:	[email protected]

Documents available

Clinical Study protocol
Download
Statistical Analysis Plan (SAP)
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

AstraZeneca Clinica Study Information

+ 800-236-9933

information.center@astrazeneca.com

Investigators

Principal Investigator

Gerard Criner

Temple University School of Medicine, 3401 North Broad Street, Suite 745 PP, Philadelphia, PA 19140

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Clinical Study protocol

Statistical Analysis Plan (SAP)

Trial Results Summaries