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Clinical Trial Results:
A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)

Summary
EudraCT number	2014-001086-27
Trial protocol	GB CZ PL DE SE BG ES FR
Global end of trial date	14 Aug 2018

Results information
Results version number	v2(current)
This version publication date	25 Jul 2019
First version publication date	27 Dec 2018
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D3250C00021

ISRCTN number

US NCT number

NCT02258542

WHO universal trial number (UTN)

U1111-1162-2422

Sponsor organisation name

AstraZeneca AB

Sponsor organisation address

Vastra Malarehamnen 9, Sodertalje, Sweden, 151 85

Public contact

Ubaldo Martin, Global Clinical Lead Benralizumab, AstraZeneca AB, Ubaldo.Martin@astrazeneca.com

Scientific contact

AZ Clinical Study Information, AstraZeneca AB, 46 855 326000, information.center@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

31 Jan 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

14 Aug 2018

Was the trial ended prematurely?

Main objective of the trial

1. To assess the safety and tolerability of 2 dosing regimens of benralizumab for adult patients during the 56-week treatment period and through the follow-up period (16 weeks from day of last dose) 2. To assess the safety and tolerability of 2 dosing regimens of benralizumab for adolescent patients during the 108-week treatment period and through the follow-up period (16 weeks from day of last dose)

Protection of trial subjects

Data safety monitoring board (DSMB) evaluates cumulative safety and other clinical trial data at regular intervals and making appropriate recommendations based on the available data. The DSMB functions independently of all other individuals associated with the conduct of the studies, including the study sponsor, AstraZeneca. The committee operates in accordance with a DSMB charter.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 220

Country: Number of subjects enrolled

Australia: 36

Country: Number of subjects enrolled

Brazil: 31

Country: Number of subjects enrolled

Bulgaria: 93

Country: Number of subjects enrolled

Canada: 74

Country: Number of subjects enrolled

Chile: 30

Country: Number of subjects enrolled

Czech Republic: 42

Country: Number of subjects enrolled

France: 83

Country: Number of subjects enrolled

Germany: 178

Country: Number of subjects enrolled

Japan: 73

Country: Number of subjects enrolled

Peru: 50

Country: Number of subjects enrolled

Philippines: 60

Country: Number of subjects enrolled

Poland: 355

Country: Number of subjects enrolled

Romania: 41

Country: Number of subjects enrolled

Russian Federation: 130

Country: Number of subjects enrolled

South Africa: 17

Country: Number of subjects enrolled

Korea, Republic of: 124

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

Sweden: 8

Country: Number of subjects enrolled

Turkey: 42

Country: Number of subjects enrolled

Ukraine: 114

Country: Number of subjects enrolled

United Kingdom: 35

Country: Number of subjects enrolled

United States: 254

Country: Number of subjects enrolled

Vietnam: 8

Worldwide total number of subjects

2133

EEA total number of subjects

870

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1742

From 65 to 84 years

319

85 years and over

Subject disposition

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Recruitment details

2133 patients entered BORA. 10 were excluded due to a GCP breach. Of remaining 2123 patients, 1926 entered from SIROCCO/CALIMA and 197 from ZONDA. 2 patients were not treated, and a total of 447 patients (348 SIROCCO/CALIMA and 99 ZONDA) were later enrolled into MELTEMI without completing the follow-up in BORA, so not in the main analyses.

Screening details

953 participants from SIROCCO/CALIMA receive benralizumab 30 mg at every 4 weeks during BORA. 971 participants from SIROCCO/CALIMA receive treatment at every 8 weeks during BORA. 100 participants from ZONDA receive treatment at every 4 weeks during BORA. 97 participants from study ZONDA receive treatment at every 8 weeks during BORA.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks

Arm description

Benralizumab administered subcutaneously every 4 weeks

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

30 mg

SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks

Arm description

Benralizumab administered subcutaneously every 8 weeks

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

30 mg

ZONDA - Benralizumab 30 mg q.4 weeks

Arm description

Benralizumab administered subcutaneously every 4 weeks

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

30 mg

ZONDA - Benralizumab 30 mg q.8 weeks

Arm description

Benralizumab administered subcutaneously every 8 weeks

Arm type

Experimental

Investigational medicinal product name

Benralizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

30 mg

Number of subjects in period 1 ^[1]	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Started	953	973	100	97
Treated	953	971	100	97
Completed	911	924	92	92
Not completed	42	49	8	5
Adverse event, serious fatal	5	4	-	1
Consent withdrawn by subject	20	20	7	1
Eligibility criteria not fulfilled	-	2	-	-
Adverse event, non-fatal	3	4	-	-
study specific discount. criteria	1	1	-	-
Lost to follow-up	5	12	1	2
eg. not made to the visit	7	4	-	1
Protocol deviation	1	2	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 10 patients in total were excluded from all analyses due to GCP breach.

Baseline characteristics

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Reporting group title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks

Reporting group description

Benralizumab administered subcutaneously every 8 weeks

Reporting group title

ZONDA - Benralizumab 30 mg q.4 weeks

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

ZONDA - Benralizumab 30 mg q.8 weeks

Reporting group description

Benralizumab administered subcutaneously every 8 weeks

Reporting group values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	Total
Number of subjects	953	973	100	97	2123
Age categorical
Units: Subjects
Adolescents (12-17 years)	21	51	0	0	72
Adults (18-64 years)	773	790	86	83	1732
From 65-84 years	159	132	14	14	319
Age Continuous
Units: Years
arithmetic mean (standard deviation)	51.1 ( 13.79 )	48.9 ( 15.53 )	49.7 ( 10.35 )	52.7 ( 8.90 )	-
Sex: Female, Male
Units: Subjects
Female	612	584	58	61	1315
Male	341	389	42	36	808
Race/Ethnicity, Customized
Units: Subjects
White	753	774	96	88	1711
Black and African American	25	30	0	2	57
Asian	143	139	4	7	293
Other	32	30	0	0	62

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment-adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment-adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment- adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Subject analysis sets values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects	518	265	512	281	31	18	31	18	14	11	32	29
Age categorical
Units: Subjects
Adolescents (12-17 years)	12	9	25	26	0	0	0	0	14	11	32	29
Adults (18-64 years)	421	213	421	211	30	16	11	17	0	0	0	0
From 65-84 years	85	43	66	44	1	2	20	1	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	51.7 ( 13.26 )	49.9 ( 14.73 )	49.3 ( 14.81 )	48.2 ( 16.77 )	47.9 ( 10.42 )	52.7 ( 9.77 )	54.3 ( 8.39 )	49.9 ( 9.30 )	14.6 ( 1.39 )	14.5 ( 1.51 )	14.4 ( 1.85 )	13.9 ( 1.77 )
Sex: Female, Male
Units: Subjects
Female	339	164	307	163	13	14	20	9	6	4	13	12
Male	179	101	205	118	18	4	11	9	8	7	19	17
Race/Ethnicity, Customized
Units: Subjects
White	398	201	388	224	28	17	26	16	10	8	27	28
Black and African American	6	10	12	7	0	0	0	1	1	2	1	0
Asian	94	44	92	44	3	1	5	1	0	0	0	1
Other	20	10	20	6	0	0	0	0	3	1	4	0

End points

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Reporting group title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks

Reporting group description

Benralizumab administered subcutaneously every 8 weeks

Reporting group title

ZONDA - Benralizumab 30 mg q.4 weeks

Reporting group description

Benralizumab administered subcutaneously every 4 weeks

Reporting group title

ZONDA - Benralizumab 30 mg q.8 weeks

Reporting group description

Benralizumab administered subcutaneously every 8 weeks

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

Subject analysis set title

SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

Subject analysis set title

ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment-adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment-adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment- adolescents only

Subject analysis set title

SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents

Subject analysis set type

Full analysis

Subject analysis set description

Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

Primary: Change from baseline in Basophils, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in Basophils, Full analysis set, Excluding MELTEMI patients ^[1]

End point description

Change from baseline in hematologic lab parameter of Basophils.

End point type

Primary

End point timeframe

Week 56

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	691	703	39	42
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.005 ( 0.0223 )	-0.005 ( 0.0239 )	-0.007 ( 0.0283 )	-0.005 ( 0.0244 )

No statistical analyses for this end point

Primary: Change from baseline in Basophils, Full analysis set, adolescents only

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End point title

Change from baseline in Basophils, Full analysis set, adolescents only ^[2] ^[3]

End point description

Change from baseline in hematologic lab parameter of Basophils.

End point type

Primary

End point timeframe

Week 108

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	16	45
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.006 ( 0.0145 )	0.001 ( 0.0208 )

No statistical analyses for this end point

Primary: Change from baseline in Leukocytes, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in Leukocytes, Full analysis set, Excluding MELTEMI patients ^[4]

End point description

Change from baseline in hematologic lab parameter of Leukocytes.

End point type

Primary

End point timeframe

Week 56

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	695	710	39	42
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.344 ( 2.0412 )	-0.128 ( 1.8614 )	-0.808 ( 1.8177 )	-0.507 ( 3.3612 )

No statistical analyses for this end point

Primary: Change from baseline in Leukocytes, Full analysis set, adolescents only

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End point title

Change from baseline in Leukocytes, Full analysis set, adolescents only ^[5] ^[6]

End point description

Change from baseline in hematologic lab parameter of Leukocytes.

End point type

Primary

End point timeframe

Week 108

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	16	47
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.487 ( 1.7289 )	-0.079 ( 1.8432 )

No statistical analyses for this end point

Primary: Change from baseline in Lymphocytes, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in Lymphocytes, Full analysis set, Excluding MELTEMI patients ^[7]

End point description

Change from baseline in hematologic lab parameter of Lymphocytes.

End point type

Primary

End point timeframe

Week 56

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	691	703	39	42
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.032 ( 0.6242 )	0.003 ( 0.5402 )	-0.093 ( 0.6403 )	0.007 ( 0.6864 )

No statistical analyses for this end point

Primary: Change from baseline in Lymphocytes, Full analysis set, adolescents only

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End point title

Change from baseline in Lymphocytes, Full analysis set, adolescents only ^[8] ^[9]

End point description

Change from baseline in hematologic lab parameter of Lymphocytes.

End point type

Primary

End point timeframe

Week 108

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	16	45
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.180 ( 0.6946 )	-0.070 ( 0.6671 )

No statistical analyses for this end point

Primary: Change from baseline in Neutrophils, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in Neutrophils, Full analysis set, Excluding MELTEMI patients ^[10]

End point description

Change from baseline in hematologic lab parameter of Neutrophils.

End point type

Primary

End point timeframe

Week 56

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	691	703	39	42
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.171 ( 1.8746 )	0.013 ( 1.7024 )	-0.501 ( 1.7096 )	-0.368 ( 3.2057 )

No statistical analyses for this end point

Primary: Change from baseline in Neutrophils, Full analysis set, adolescents only

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End point title

Change from baseline in Neutrophils, Full analysis set, adolescents only ^[11] ^[12]

End point description

Change from baseline in hematologic lab parameter of Neutrophils.

End point type

Primary

End point timeframe

Week 108

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	16	45
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.451 ( 1.7645 )	0.242 ( 1.8469 )

No statistical analyses for this end point

Primary: Change from baseline in Eosinophils, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in Eosinophils, Full analysis set, Excluding MELTEMI patients ^[13]

End point description

Change from baseline in hematologic lab parameter of Eosinophils.

End point type

Primary

End point timeframe

Week 56

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	691	703	39	42
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.1220 ( 0.30599 )	-0.1271 ( 0.26161 )	-0.1451 ( 0.30766 )	-0.1664 ( 0.35139 )

No statistical analyses for this end point

Primary: Change from baseline in Eosinophils, Full analysis set, adolescents only

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End point title

Change from baseline in Eosinophils, Full analysis set, adolescents only ^[14] ^[15]

End point description

Change from baseline in hematologic lab parameter of Eosinophils.

End point type

Primary

End point timeframe

Week 108

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	16	45
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-0.1294 ( 0.27973 )	-0.1838 ( 0.3381 )

No statistical analyses for this end point

Primary: Change from baseline in ALT, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in ALT, Full analysis set, Excluding MELTEMI patients ^[16]

End point description

Change from baseline in chemistry tests ALT.

End point type

Primary

End point timeframe

Week 56

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	684	712	37	43
Units: ukat/L
arithmetic mean (standard deviation)	-0.007 ( 0.2102 )	0.017 ( 0.4651 )	-0.064 ( 0.3547 )	-0.023 ( 0.1940 )

No statistical analyses for this end point

Primary: Change from baseline in ALT, Full analysis set, adolescents only

Top of page

End point title

Change from baseline in ALT, Full analysis set, adolescents only ^[17] ^[18]

End point description

Change from baseline in hematologic lab parameter of ALT.

End point type

Primary

End point timeframe

Week 108

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	17	51
Units: ukat/L
arithmetic mean (standard deviation)	0.048 ( 0.2195 )	0.034 ( 0.2312 )

No statistical analyses for this end point

Primary: Change from baseline in AST, Full analysis set, Excluding MELTEMI patients

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End point title

Change from baseline in AST, Full analysis set, Excluding MELTEMI patients ^[19]

End point description

Change from baseline in chemistry tests AST.

End point type

Primary

End point timeframe

Week 56

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	684	712	37	43
Units: ukat/L
arithmetic mean (standard deviation)	-0.005 ( 0.1431 )	0.004 ( 0.3303 )	-0.027 ( 0.2291 )	-0.026 ( 0.1178 )

No statistical analyses for this end point

Primary: Change from baseline in AST, Full analysis set, adolescents only

Top of page

End point title

Change from baseline in AST, Full analysis set, adolescents only ^[20] ^[21]

End point description

Change from baseline in hematologic lab parameter of AST.

End point type

Primary

End point timeframe

Week 108

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	17	50
Units: ukat/L
arithmetic mean (standard deviation)	-0.006 ( 0.1196 )	-0.013 ( 0.1297 )

No statistical analyses for this end point

Primary: Change from baseline in Bilirubin, Full analysis set, Excluding MELTEMI patients

Top of page

End point title

Change from baseline in Bilirubin, Full analysis set, Excluding MELTEMI patients ^[22]

End point description

Change from baseline in chemistry test Bilirubin.

End point type

Primary

End point timeframe

Week 56

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	685	712	37	43
Units: umol/L
arithmetic mean (standard deviation)	0.187 ( 3.6261 )	0.391 ( 3.9945 )	0.146 ( 2.8094 )	0.279 ( 3.8765 )

No statistical analyses for this end point

Primary: Change from baseline in Bilirubin, Full analysis set, adolescents only

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End point title

Change from baseline in Bilirubin, Full analysis set, adolescents only ^[23] ^[24]

End point description

Change from baseline in hematologic lab parameter of Bilirubin.

End point type

Primary

End point timeframe

Week 108

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	17	51
Units: umol/L
arithmetic mean (standard deviation)	2.221 ( 8.3453 )	0.202 ( 3.6575 )

No statistical analyses for this end point

Secondary: Number of overall patients with asthma exacerbations during study period

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End point title

Number of overall patients with asthma exacerbations during study period

End point description

Annual asthma exacerbation rate, where an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic corticosteroids for at least 3 days, and/or an in patient hospitalization, and/or an emergency department or urgent care visit

End point type

Secondary

End point timeframe

From week 0 to week 56 in study treatment period and through the follow up period (16 weeks from day of last dose)

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	783	793	49	49	518	265	512	281	31	18	31	18
Units: participants
Sirocco/Calima eos>=300/μL\|# exacerb.	159	170	0	0	99	60	104	66	0	0	0	0
Sirocco/Calima eos<300/μL\|# exacerb.	113	97	0	0	69	44	65	32	0	0	0	0
Zonda\|# exacerb.	0	0	17	24	0	0	0	0	12	5	13	11

No statistical analyses for this end point

Secondary: Number of overall patients with asthma exacerbations during study period, adolescents only

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End point title

Number of overall patients with asthma exacerbations during study period, adolescents only ^[25]

End point description

End point type

Secondary

End point timeframe

From week 0 to week 108 in study treatment period and through the follow up period (16 weeks from day of last dose)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	25	61	14	11	32	29
Units: participants
Sirocco/Calima eos>=300/μL\|# exacerb.	8	8	2	6	3	5
Sirocco/Calima eos<300/μL\|# exacerb.	0	11	0	0	5	6

No statistical analyses for this end point

Secondary: Change from baseline in pre-brochodilator FEV1 (L)

Top of page

End point title

Change from baseline in pre-brochodilator FEV1 (L)

End point description

Change from baseline to Week 56 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1).

End point type

Secondary

End point timeframe

Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	665 ^[26]	660 ^[27]	38 ^[28]	43 ^[29]	444 ^[30]	221 ^[31]	440 ^[32]	220 ^[33]	27 ^[34]	11 ^[35]	28 ^[36]	15 ^[37]
Units: Liter
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	0.038 ( 0.346 )	0.040 ( 0.356 )	0 ( 0 )	0 ( 0 )	-0.006 ( 0.295 )	0.131 ( 0.422 )	0.019 ( 0.317 )	0.081 ( 0.419 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL\|	-0.017 ( 0.345 )	-0.001 ( 0.312 )	0 ( 0 )	0 ( 0 )	-0.021 ( 0.376 )	-0.011 ( 0.280 )	-0.015 ( 0.293 )	0.030 ( 0.350 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Number of Zonda Patients\|	0 ( 0 )	0 ( 0 )	0.057 ( 0.412 )	-0.012 ( 0.314 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0.013 ( 0.354 )	0.167 ( 0.533 )	-0.093 ( 0.280 )	0.138 ( 0.329 )

Notes
[26] - 439 for EOS>=300 226 for EOS<300
[27] - 442 for EOS>=300 218 for EOS<300
[28] - Over all EOS
[29] - Over all EOS
[30] - 297 for EOS>=300 147 for EOS<300
[31] - 142 for EOS>=300 79 for EOS<300
[32] - 291 for EOS>=300 149 for EOS<300
[33] - 151 for EOS>=300 69 for EOS<300
[34] - Over all EOS
[35] - Over all EOS
[36] - Over all EOS
[37] - Over all EOS

No statistical analyses for this end point

Secondary: Change from baseline in pre-brochodilator FEV1 (L), adolescents only

Top of page

End point title

Change from baseline in pre-brochodilator FEV1 (L), adolescents only ^[38]

End point description

Change from baseline to Week 108 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1).

End point type

Secondary

End point timeframe

Week 108

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	17	51	8 ^[39]	9 ^[40]	25 ^[41]	26 ^[42]
Units: Liter
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-0.020 ( 0.375 )	0.496 ( 0.502 )	0.205 ( 0.289 )	-0.189 ( 0.354 )	0.578 ( 0.608 )	0.413 ( 0.375 )
Sirocco/Calima patients with eos<300/μL\|	0.597 ( 0.561 )	0.147 ( 0.444 )	0.325 ( 0.431 )	1.140 ( 0 )	0.047 ( 0.340 )	0.240 ( 0.519 )

Notes
[39] - 6 for EOS>=300 2 for EOS<300
[40] - 8 for EOS>=300 1 for EOS<300
[41] - 13 for EOS>=300 12 for EOS<300
[42] - 13 for EOS>=300 13 for EOS<300

No statistical analyses for this end point

Secondary: Change from baseline in post-brochodilator FEV1 (L)

Top of page

End point title

Change from baseline in post-brochodilator FEV1 (L) ^[43]

End point description

Change from baseline to Week 56 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1).

End point type

Secondary

End point timeframe

Week 56

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	659 ^[44]	652 ^[45]	439 ^[46]	220 ^[47]	438 ^[48]	214 ^[49]
Units: Liter
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-0.015 ( 0.354 )	-0.004 ( 0.329 )	-0.066 ( 0.280 )	0.089 ( 0.455 )	-0.029 ( 0.281 )	0.045 ( 0.401 )
Sirocco/Calima patients with eos<300/μL\|	-0.046 ( 0.350 )	-0.015 ( 0.316 )	-0.058 ( 0.379 )	-0.024 ( 0.289 )	-0.043 ( 0.273 )	0.049 ( 0.394 )

Notes
[44] - 440 for EOS>=300 219 for EOS<300
[45] - 443 for EOS>=300 209 for EOS<300
[46] - 296 for EOS >=300 143 for EOS<300
[47] - 144 for EOS>=300 76 for EOS<300
[48] - 292 for EOS>=300 146 for EOS<300
[49] - 151 for EOS>=300 63 for EOS<300

No statistical analyses for this end point

Secondary: Change from baseline in Post-bronchodilator FEV1 (L), adolescents only

Top of page

End point title

Change from baseline in Post-bronchodilator FEV1 (L), adolescents only ^[50]

End point description

Change from baseline to Week 108 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1).

End point type

Secondary

End point timeframe

Week 108

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	17	51	8 ^[51]	9 ^[52]	25 ^[53]	26 ^[54]
Units: Liter
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-0.201 ( 0.458 )	0.448 ( 0.712 )	-0.062 ( 0.537 )	-0.305 ( 0.394 )	0.603 ( 0.749 )	0.279 ( 0.659 )
Sirocco/Calima patients with eos<300/μL\|	0.543 ( 0.444 )	0.111 ( 0.454 )	0.375 ( 0.474 )	0.880 ( 0 )	-0.006 ( 0.327 )	0.218 ( 0.536 )

Notes
[51] - 6 for EOS>=300 2 for EOS<300
[52] - 8 for EOS>=300 1 for EOS<300
[53] - 13 for EOS>=300 12 for EOS<300
[54] - 13 for EOS>=300 13 for EOS<300

No statistical analyses for this end point

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients

Top of page

End point title

Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients

End point description

Asthma Control Questionnaire 6 (ACQ-6) contains 1 bronchodilator use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses.

End point type

Secondary

End point timeframe

Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	671 ^[55]	664 ^[56]	39 ^[57]	43 ^[58]	447 ^[59]	224 ^[60]	444 ^[61]	220 ^[62]	28 ^[63]	11 ^[64]	28 ^[65]	15 ^[66]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-0.09 ( 0.91 )	-0.12 ( 0.91 )	0 ( 0 )	0 ( 0 )	-0.04 ( 0.83 )	-0.20 ( 1.04 )	-0.06 ( 0.82 )	-0.25 ( 1.06 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL\|	-0.15 ( 0.86 )	-0.10 ( 0.90 )	0 ( 0 )	0 ( 0 )	-0.16 ( 0.90 )	-0.12 ( 0.80 )	-0.10 ( 0.83 )	-0.09 ( 1.06 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Number of Zonda Patients\|	0 ( 0 )	0 ( 0 )	-0.21 ( 0.87 )	-0.05 ( 1.04 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	-0.05 ( 0.89 )	-0.61 ( 0.74 )	0.15 ( 1.02 )	-0.43 ( 1.00 )

Notes
[55] - 444 for EOS>=300 227 for EOS<300
[56] - 447 for EOS>=300 217 for EOS<300
[57] - Over all EOS
[58] - Over all EOS
[59] - 298 for EOS >=300 149 for EOS<300
[60] - 146 for EOS>=300 78 for EOS<300
[61] - 294 for EOS>=300 150 for EOS<300
[62] - 153 for EOS>=300 67 for EOS<300
[63] - Over all EOS
[64] - Over all EOS
[65] - Over all EOS
[66] - Over all EOS

No statistical analyses for this end point

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, adolescents only

Top of page

End point title

Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, adolescents only ^[67]

End point description

End point type

Secondary

End point timeframe

Week 108

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	18	51	9 ^[68]	9 ^[69]	25 ^[70]	26 ^[71]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	0.16 ( 0.50 )	-0.12 ( 1.02 )	0.26 ( 0.53 )	0.06 ( 0.49 )	-0.14 ( 0.51 )	-0.10 ( 1.38 )
Sirocco/Calima patients with eos<300/μL\|	0.94 ( 0.79 )	-0.21 ( 0.76 )	-0.50 ( 0.24 )	-1.83 ( 0 )	-0.21 ( 0.78 )	-0.21 ( 0.77 )

Notes
[68] - 7 for EOS>=300 2 for EOS<300
[69] - 8 for EOS>=300 1 for EOS<300
[70] - 13 for EOS>=300 12 for EOS<300
[71] - 13 for EOS>=300 13 for EOS<300

No statistical analyses for this end point

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12)

Top of page

End point title

Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12)

End point description

Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). It contains 32 questions on a 7 point scale ranging from 7 (no impairment) to 1 (severe impairment); total score is an average of all questions. An increase in score indicates improvement.

End point type

Secondary

End point timeframe

Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	668 ^[72]	662 ^[73]	37 ^[74]	43 ^[75]	444 ^[76]	224 ^[77]	442 ^[78]	220 ^[79]	26 ^[80]	11 ^[81]	28 ^[82]	15 ^[83]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	0.08 ( 0.87 )	0.15 ( 0.94 )	0 ( 0 )	0 ( 0 )	0.02 ( 0.80 )	0.21 ( 0.98 )	0.08 ( 0.91 )	0.26 ( 1.00 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL\|	0.09 ( 0.85 )	0.11 ( 0.95 )	0 ( 0 )	0 ( 0 )	0.11 ( 0.84 )	0.03 ( 0.89 )	0.15 ( 0.90 )	0.02 ( 1.06 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Number of Zonda Patients\|	0 ( 0 )	0 ( 0 )	0.22 ( 0.92 )	0.11 ( 0.98 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0.13 ( 0.93 )	0.43 ( 0.91 )	-0.04 ( 0.94 )	0.40 ( 1.03 )

Notes
[72] - 442 for EOS>=300 226 for EOS<300
[73] - 446 for EOS>=300 216 for EOS<300
[74] - Over all EOS
[75] - Over all EOS
[76] - 296 for EOS>=300 148 for EOS<300
[77] - 146 for EOS>=300 78 for EOS<300
[78] - 293 for EOS>=300 149 for EOS<300
[79] - 153 for EOS>=300 67 for EOS<300
[80] - Over all EOS
[81] - Over all EOS
[82] - Over all EOS
[83] - Over all EOS

No statistical analyses for this end point

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), adolescents only

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End point title

Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), adolescents only ^[84]

End point description

End point type

Secondary

End point timeframe

Week 108

Notes
[84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	17	51	9 ^[85]	8 ^[86]	25 ^[87]	26 ^[88]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	0.25 ( 0.92 )	0.29 ( 0.54 )	0.60 ( 1.22 )	-0.11 ( 0.21 )	0.52 ( 0.37 )	0.06 ( 0.59 )
Sirocco/Calima patients with eos<300/μL\|	0.94 ( 0.65 )	0.42 ( 0.89 )	0.64 ( 0.55 )	1.53 ( 0 )	0.58 ( 1.01 )	0.27 ( 0.77 )

Notes
[85] - 7 for EOS>=300 2 for EOS<300
[86] - 7 for EOS>=300 1 for EOS<300
[87] - 13 for EOS>=300 12 for EOS<300
[88] - 13 for EOS>=300 13 for EOS>=300

No statistical analyses for this end point

Secondary: Change of blood eosinophil levels measurement in overall patients

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End point title

Change of blood eosinophil levels measurement in overall patients

End point description

Change from baseline to Week 56 in Blood eosinophils

End point type

Secondary

End point timeframe

Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	691 ^[89]	703 ^[90]	39 ^[91]	42 ^[92]	454 ^[93]	237 ^[94]	461 ^[95]	242 ^[96]	28 ^[97]	11 ^[98]	27 ^[99]	15 ^[100]
Units: cell/uL
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-148.6 ( 332.91 )	-154.1 ( 297.34 )	0 ( 0 )	0 ( 0 )	4.9 ( 177.42 )	-449.6 ( 360.6 )	-10.1 ( 134.7 )	-422.5 ( 330.01 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL\|	-68.4 ( 234.40 )	-74.7 ( 160.29 )	0 ( 0 )	0 ( 0 )	15.7 ( 87.04 )	-222.1 ( 325.03 )	-2.9 ( 59.11 )	-217.4 ( 198.56 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Number of Zonda Patients\|	0 ( 0 )	0 ( 0 )	-145.1 ( 307.66 )	-166.4 ( 351.39 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	2.5 ( 69.85 )	-520.9 ( 360.79 )	-17.0 ( 107.48 )	-435.3 ( 468.64 )

Notes
[89] - 462 for EOS>=300 229 for EOS<300
[90] - 464 for EOS>=300 239 for EOS<300
[91] - Over all EOS
[92] - Over all EOS
[93] - 306 for EOS>=300 148 for EOS<300
[94] - 156 for EOS>=300 81 for EOS<300
[95] - 302 for EOS>=300 159 for EOS<300
[96] - 162 for EOS>300 80 for EOS<300
[97] - Over all EOS
[98] - Over all EOS
[99] - Over all EOS
[100] - Over all EOS

No statistical analyses for this end point

Secondary: Change of blood eosinophil levels measurement in adolescents patients.

Top of page

End point title

Change of blood eosinophil levels measurement in adolescents patients. ^[101]

End point description

Change from baseline to Week 108 in Blood eosinophils.

End point type

Secondary

End point timeframe

Week 108

Notes
[101] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	14	37	7 ^[102]	7 ^[103]	21 ^[104]	16 ^[105]
Units: cell/uL
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	-139.2 ( 299.16 )	-229.4 ( 446.21 )	78.3 ( 192.19 )	-356.7 ( 215.47 )	-163.6 ( 502.76 )	-332.9 ( 349.89 )
Sirocco/Calima patients with eos<300/μL\|	5.0 ( 219.20 )	-97.9 ( 145.40 )	160.0 ( 0 )	-150.0 ( 0 )	-2.0 ( 9.19 )	-204.4 ( 152.32 )

Notes
[102] - 6 for EOS>=300 1 for EOS<300
[103] - 6 for EOS>=300 1 for EOS<300
[104] - 11 for EOS>=300 10 for EOS<300
[105] - 7 for EOS>=300 9 for EOS<300

No statistical analyses for this end point

Secondary: Change from baseline in EQ-5D-5L visual analog scale

Top of page

End point title

Change from baseline in EQ-5D-5L visual analog scale

End point description

The questionnaire included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state; thus, an increase in VAS score indicated improvement.

End point type

Secondary

End point timeframe

Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	682 ^[106]	709 ^[107]	21 ^[108]	28 ^[109]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	6.08 ( 15.68 )	6.02 ( 17.68 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL\|	4.38 ( 14.99 )	6.69 ( 15.96 )	0 ( 0 )	0 ( 0 )
Number of Zonda Patients\|	0 ( 0 )	0 ( 0 )	5.00 ( 10.35 )	1.36 ( 13.58 )

Notes
[106] - 454 for EOS>=300 228 for EOS<300
[107] - 468 for EOS>=300 241 for EOS<300
[108] - Over all EOS
[109] - Over all EOS

No statistical analyses for this end point

Secondary: Change from baseline in EQ-5D-5L visual analog scale, adolescents only

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End point title

Change from baseline in EQ-5D-5L visual analog scale, adolescents only ^[110]

End point description

End point type

Secondary

End point timeframe

Week 108

Notes
[110] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	18	48	9 ^[111]	9 ^[112]	24 ^[113]	24 ^[114]
Units: Score on a scale
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL\|	6.07 ( 12.71 )	10.72 ( 21.26 )	5.43 ( 9.73 )	6.63 ( 15.53 )	11.54 ( 26.95 )	9.83 ( 13.87 )
Sirocco/Calima patients with eos<300/μL\|	13.33 ( 17.50 )	7.52 ( 23.39 )	22.00 ( 12.73 )	-4.00 ( 0 )	10.18 ( 32.69 )	5.08 ( 10.45 )

Notes
[111] - 7 for EOS>=300 2 for EOS<300
[112] - 8 for EOS>=300 1 for EOS<300
[113] - 13 for EOS>=300 11 for EOS<300
[114] - 12 for EOS>=300 12 for EOS<300

No statistical analyses for this end point

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI)

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End point title

Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI)

End point description

The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Work productivity loss is calculated with sum of hours missed at work due to health problem and hours that affected due to health problem at work, divided by sum of hours missed due to health problem and hours actually worked, presented by percentage.

End point type

Secondary

End point timeframe

Baseline and Week 68

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	783 ^[115]	793 ^[116]	49 ^[117]	49 ^[118]
Units: percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-baseline\|	25.3 ( 24.70 )	25.0 ( 24.15 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos>=300/μL-wk 68\|	23.3 ( 26.18 )	21.0 ( 25.54 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL-baseline\|	31.0 ( 27.06 )	32.6 ( 26.29 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL-wk 68\|	32.7 ( 27.55 )	25.8 ( 24.05 )	0 ( 0 )	0 ( 0 )
Zonda Patients-baseline\|	0 ( 0 )	0 ( 0 )	23.5 ( 25.13 )	7.1 ( 10.47 )
Zonda Patients-wk 68\|	0 ( 0 )	0 ( 0 )	18.9 ( 24.94 )	21.0 ( 27.13 )

Notes
[115] - BS: 234 for EOS>=300 WK68: 236 for EOS>=300 BS: 101 for EOS<300 WK68: 97 for EOS<300
[116] - BS: 217 for EOS>=300 WK68: 217 for EOS>=300 BS: 93 for EOS<300 WK68: 96 for EOS<300
[117] - BS: 16 WK68: 19
[118] - BS: 17 WK68: 20

No statistical analyses for this end point

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only

Top of page

End point title

Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only ^[119]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 108

Notes
[119] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	25	61	14	11	32	29
Units: Percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-baseline\|	10.0 ( 0 )	77.5 ( 24.75 )	10.0 ( 0 )	0 ( 0 )	60.0 ( 0 )	95.0 ( 0 )
Sirocco/Calima patients with eos>=300/μL-wk 108\|	3 ( 3.3 )	15.0 ( 7.07 )	0.0 ( 0.00 )	10.0 ( 0 )	20.0 ( 0 )	10.0 ( 0 )
Sirocco/Calima patients with eos<300/μL-baseline\|	0 ( 0 )	55.0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	55.0 ( 0 )
Sirocco/Calima patients with eos<300/μL-wk-108\|	0 ( 0 )	8.0 ( 8.37 )	0 ( 0 )	0 ( 0 )	0.0 ( 0.00 )	13.3 ( 5.77 )

No statistical analyses for this end point

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ)

Top of page

End point title

Classroom productivity loss using Classroom Impairment Questionnaire (CIQ) ^[120]

End point description

The WPAI (+CIQ) is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Classroom productivity loss is calculated with sum of hours missed for classes due to health problem and hours that affected due to health problem in classes, divided by sum of hours missed due to health problem and hours actually attended classes, presented by percentage.

End point type

Secondary

End point timeframe

Baseline and Week 56

Notes
[120] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	25 ^[121]	61 ^[122]
Units: Percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-Baseline\|	13.0 ( 19.14 )	30.7 ( 31.41 )
Sirocco/Calima patients with eos>=300/μL-wk 56\|	3.8 ( 7.44 )	15.2 ( 20.69 )
Sirocco/Calima patients with eos<300/μL-Baseline\|	42.1 ( 32.50 )	35.4 ( 23.92 )
Sirocco/Calima patients with eos<300/μL-wk 56\|	5.0 ( 7.07 )	17.1 ( 20.06 )

Notes
[121] - BS: 11 for EOS>=300 WK56: 8 for EOS>=300 BS: 4 for EOS<300 WK56: 2 for EOS<300
[122] - BS: 23 for EOS>=300 WK56: 24 for EOS>=300 BS: 19 for EOS<300 WK56: 24 for EOS<300

No statistical analyses for this end point

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ), adolescents only

Top of page

End point title

Classroom productivity loss using Classroom Impairment Questionnaire (CIQ), adolescents only ^[123]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 108

Notes
[123] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	25	61	14	11	32	29
Units: Percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-baseline\|	13.0 ( 19.14 )	30.7 ( 31.41 )	18.8 ( 24.08 )	6.0 ( 8.94 )	31.9 ( 32.10 )	29.3 ( 32.13 )
Sirocco/Calima patients with eos>=300/μL-wk 108\|	9.5 ( 12.98 )	12.3 ( 21.62 )	4.9 ( 6.82 )	15.2 ( 17.55 )	5.4 ( 8.32 )	18.6 ( 27.94 )
Sirocco/Calima patients with eos<300/μL-baseline\|	42.1 ( 32.50 )	35.4 ( 23.92 )	25.0 ( 35.36 )	59.3 ( 27.27 )	36.5 ( 28.23 )	34.4 ( 20.82 )
Sirocco/Calima patients with eos<300/μL-wk-108\|	21.5 ( 30.41 )	11.5 ( 14.66 )	21.5 ( 30.41 )	0 ( 0 )	12.5 ( 18.10 )	10.6 ( 11.68 )

No statistical analyses for this end point

Secondary: Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI)

Top of page

End point title

Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI)

End point description

The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. The WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

End point type

Secondary

End point timeframe

Baseline and Week 68

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	783 ^[124]	793 ^[125]	49 ^[126]	49 ^[127]
Units: percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-baseline\|	31.3 ( 26.44 )	31.2 ( 25.63 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos>=300/μL-wk 68\|	26.6 ( 26.14 )	24.4 ( 25.26 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL-baseline\|	39.6 ( 25.75 )	36.3 ( 25.72 )	0 ( 0 )	0 ( 0 )
Sirocco/Calima patients with eos<300/μL-wk 68\|	33.6 ( 26.55 )	32.7 ( 26.58 )	0 ( 0 )	0 ( 0 )
Zonda Patients-baseline\|	0 ( 0 )	0 ( 0 )	31.5 ( 29.49 )	24.5 ( 29.08 )
Zonda Patients-wk 68\|	0 ( 0 )	0 ( 0 )	28.4 ( 27.85 )	39.0 ( 34.36 )

Notes
[124] - BS: 518 for EOS>=300 WK68: 458 for EOS>=300 BS: 261 for EOS<300 WK68: 239 for EOS<300
[125] - BS: 524 for EOS>=300 WK68: 454 for EOS>=300 BS: 264 for EOS<300 WK68: 220 for EOS<300
[126] - BS: 26 WK68: 38
[127] - BS: 31 WK68: 41

No statistical analyses for this end point

Secondary: Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only

Top of page

End point title

Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only ^[128]

End point description

The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. The WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

End point type

Secondary

End point timeframe

Baseline and Week 108

Notes
[128] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	25	61	14	11	32	29
Units: Percentage
arithmetic mean (standard deviation)
Sirocco/Calima patients with eos>=300/μL-baseline\|	14.5 ( 22.59 )	29.7 ( 29.15 )	21.8 ( 27.86 )	5.6 ( 8.82 )	25.3 ( 23.75 )	35.0 ( 34.81 )
Sirocco/Calima patients with eos>=300/μL-wk 108\|	6.0 ( 9.86 )	12.3 ( 19.25 )	7.1 ( 11.13 )	5.0 ( 9.26 )	5.4 ( 8.77 )	19.2 ( 24.31 )
Sirocco/Calima patients with eos<300/μL-baseline\|	36.0 ( 27.02 )	31.3 ( 21.29 )	23.3 ( 25.17 )	55.0 ( 21.21 )	30.7 ( 21.20 )	32.0 ( 22.10 )
Sirocco/Calima patients with eos<300/μL-wk-108\|	13.3 ( 11.55 )	12.8 ( 14.87 )	10.0 ( 14.14 )	20.0 ( 0 )	14.2 ( 18.81 )	11.5 ( 10.68 )

No statistical analyses for this end point

Secondary: Number of patients who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period

Top of page

End point title

Number of patients who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period

End point description

Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma

End point type

Secondary

End point timeframe

From week 0 to week 68 in study treatment period and through the follow up period (16 weeks from day of last dose)

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	519 ^[129]	527 ^[130]	49 ^[131]	49 ^[132]
Units: Participants
Sirocco/Calima patients with eos>=300/μL\|	193	198	0	0
Sirocco/Calima patients with eos<300/μL\|	118	102	0	0
Number of Zonda Patients\|	0	0	20	25

Notes
[129] - 519 for EOS>=300 264 for EOS<300
[130] - 527 for EOS>=300 266 for EOS<300
[131] - Over all EOS
[132] - Over all EOS

No statistical analyses for this end point

Secondary: Number of patients who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period, adolescents only

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End point title

Number of patients who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period, adolescents only ^[133]

End point description

Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma

End point type

Secondary

End point timeframe

Baseline and Week 108

Notes
[133] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	25	61	14	11	32	29
Units: Participants
Sirocco/Calima patients with eos>=300/μL\|	7	14	2	5	7	7
Sirocco/Calima patients with eos<300/μL\|	1	12	0	1	7	5

No statistical analyses for this end point

Secondary: Pre-dose benralizumab concentration in serum during the treatment phase of the safety study

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End point title

Pre-dose benralizumab concentration in serum during the treatment phase of the safety study

End point description

Endpoint: Pharmacokinetic (PK) parameters

End point type

Secondary

End point timeframe

Week 0 and Week 56

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4	SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8	SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4	ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo	ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8	ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
Number of subjects analysed	514 ^[134]	263 ^[135]	511 ^[136]	279 ^[137]	31 ^[138]	16 ^[139]	31 ^[140]	17 ^[141]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Baseline	714.25 ( 311.38 )	0 ( 0 )	142.92 ( 353.94 )	0 ( 0 )	964.21 ( 224.01 )	0 ( 0 )	692.91 ( 205.97 )	0 ( 0 )
Week 56	930.01 ( 200.59 )	865.93 ( 242.55 )	173.95 ( 269.62 )	162.03 ( 295.05 )	823.62 ( 239.39 )	1160.58 ( 48.82 )	247.26 ( 133.0 )	139.35 ( 274.98 )

Notes
[134] - 507 for Baseline 442 for Week 56
[135] - 260 for Baseline 225 for Week 56
[136] - 503 for Baseline 440 for Week 56
[137] - 275 for Baseline 215 for Week 56
[138] - 31 for Baseline 27 for Week 56
[139] - 16 for Baseline 10 for Week 56
[140] - 30 for Baseline 27 for Week 56
[141] - 17 for Baseline 15 for Week 56

No statistical analyses for this end point

Secondary: Pre-dose benralizumab concentration in serum during the treatment phase of the safety study, adolescents only

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End point title

Pre-dose benralizumab concentration in serum during the treatment phase of the safety study, adolescents only

End point description

Endpoint: Pharmacokinetic (PK) parameters

End point type

Secondary

End point timeframe

Baseline and Week 108

End point values	SIROCCO/CALIMA - Benra 30 mg q.4 - Pre Benra q.4-adolescents	SIROCCO/CALIMA - Benra 30 mg q.4 - Predecessor Pbo-adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Pre Benra q.8- adolescents	SIROCCO/CALIMA - Benra 30 mg q.8 - Predecessor Pbo-adolescents
Number of subjects analysed	14	11	32	29
Units: ng/mL
geometric mean (geometric coefficient of variation)
Baseline	725.55 ( 589.57 )	0 ( 0 )	218.53 ( 286.39 )	0 ( 0 )
Week 108	383.73 ( 9364.83 )	853.51 ( 314.40 )	436.85 ( 858.56 )	524.39 ( 284.63 )

No statistical analyses for this end point

Secondary: Number of patients with Anti-drug antibodies (ADA) responses during the study

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End point title

Number of patients with Anti-drug antibodies (ADA) responses during the study

End point description

Assessments for the presence of ADA and nAb throughout study

End point type

Secondary

End point timeframe

From week 0 to week 56 in study treatment period (adults) and plus 16 weeks the follow up period; From week 0 to week 108-week in study treatment period (adolescents) and plus 16 weeks the follow up period

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks	ZONDA - Benralizumab 30 mg q.4 weeks	ZONDA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	783	793	49	49
Units: Participants
Positive at any visit\|	80	93	4	8
Base- and Post-baseline Positive\|	23	41	2	4
Newly Persistently Positive\|	28	34	1	3
Stable persistently positive\|	21	29	2	2
Newly treatment-induced positive\|	38	41	2	2
ADA treatment boosted positive\|	6	6	0	1
Decreased in titre\|	17	9	2	1
Only post-baseline positive\|	48	48	2	1
ADA incidence\|	44	47	2	3
Transiently Positive\|	22	26	1	3
Only baseline positive\|	9	4	0	0
nAb positive\|	57	75	3	4

No statistical analyses for this end point

Secondary: Number of patients with Anti-drug antibodies (ADA) responses during the study, adolescents only.

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End point title

Number of patients with Anti-drug antibodies (ADA) responses during the study, adolescents only. ^[142]

End point description

Assessments for the presence of ADA and nAb throughout study

End point type

Secondary

End point timeframe

From week 0 to week 108 study treatment period (adults) and plus 16 weeks the follow up period; From week 0 to week 108-week in study treatment period (adolescents) and plus 16 weeks the follow up period

Notes
[142] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is safety study and use safety endpoints as primary, only descriptive summary is planned. No statistical power or hypothesis testing is planned.

End point values	SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks	SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
Number of subjects analysed	25	61
Units: Participants
Positive at any visit\|	1	5
Base- and Post-baseline Positive\|	0	3
Newly Persistently Positive\|	0	2
Stable persistently positive\|	0	3
Newly treatment-induced positive\|	1	1
ADA treatment boosted positive\|	0	2
Decreased in titre\|	0	2
Only post-baseline positive\|	1	2
ADA incidence\|	1	3
Transiently Positive\|	1	0
Only baseline positive\|	0	0
nAb positive\|	57	5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug until last study visit

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Sirocco/Calima - Benralizumab 30 mg q.4 weeks

Reporting group description

Reporting group title

Sirocco/Calima - Benralizumab 30 mg q.8 weeks

Reporting group description

Reporting group title

Zonda - Benralizumab 30 mg q.4 weeks

Reporting group description

Reporting group title

Zonda - Benralizumab 30 mg q.8 weeks

Reporting group description

Serious adverse events	Sirocco/Calima - Benralizumab 30 mg q.4 weeks	Sirocco/Calima - Benralizumab 30 mg q.8 weeks	Zonda - Benralizumab 30 mg q.4 weeks	Zonda - Benralizumab 30 mg q.8 weeks
Total subjects affected by serious adverse events
subjects affected / exposed	102 / 783 (13.03%)	94 / 793 (11.85%)	10 / 49 (20.41%)	9 / 49 (18.37%)
number of deaths (all causes)	5	4	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign neoplasm of thyroid gland
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma stage II
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal cavity cancer
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian germ cell teratoma benign
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Solid pseudopapillary tumour of the pancreas
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign neoplasm of eyelid
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer stage 0
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine benign neoplasm
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipoma
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteochondroma
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 783 (0.00%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thymoma
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 783 (0.13%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive emergency
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Food allergy
subjects affected / exposed	0 / 783 (0.00%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical polyp
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal fistula
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	36 / 783 (4.60%)	26 / 793 (3.28%)	3 / 49 (6.12%)	2 / 49 (4.08%)
occurrences causally related to treatment / all	0 / 40	1 / 31	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Asthmatic crisis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Middle lobe syndrome
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	2 / 783 (0.26%)	2 / 793 (0.25%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	1 / 783 (0.13%)	2 / 793 (0.25%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Investigations
Endocrine test abnormal
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthropod bite
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone contusion
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Femur fracture
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 783 (0.13%)	2 / 793 (0.25%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 783 (0.13%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery insufficiency
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular extrasystoles
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 783 (0.00%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Lumbosacral radiculopathy
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Hypochromic anaemia
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Barrett's oesophagus
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral hernia strangulated
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 783 (0.26%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema nodosum
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pemphigoid
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rosacea
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria papular
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperparathyroidism
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaw cyst
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 783 (0.00%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lower respiratory tract infection viral
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 783 (0.26%)	4 / 793 (0.50%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative abscess
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 783 (0.26%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 783 (0.26%)	2 / 793 (0.25%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 783 (0.13%)	5 / 793 (0.63%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 783 (0.00%)	1 / 793 (0.13%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Sinusitis bacterial
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 783 (0.13%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	1 / 49 (2.04%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	2 / 783 (0.26%)	0 / 793 (0.00%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Sirocco/Calima - Benralizumab 30 mg q.4 weeks	Sirocco/Calima - Benralizumab 30 mg q.8 weeks	Zonda - Benralizumab 30 mg q.4 weeks	Zonda - Benralizumab 30 mg q.8 weeks
Total subjects affected by non serious adverse events
subjects affected / exposed	543 / 783 (69.35%)	557 / 793 (70.24%)	36 / 49 (73.47%)	39 / 49 (79.59%)
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 783 (0.00%)	0 / 793 (0.00%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	0	0	0	2
Blood pressure increased
subjects affected / exposed	4 / 783 (0.51%)	3 / 793 (0.38%)	1 / 49 (2.04%)	2 / 49 (4.08%)
occurrences all number	5	3	1	2
Vascular disorders
Hypertension
subjects affected / exposed	31 / 783 (3.96%)	28 / 793 (3.53%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	32	32	0	2
Peripheral venous disease
subjects affected / exposed	1 / 783 (0.13%)	3 / 793 (0.38%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	1	3	0	2
Nervous system disorders
Headache
subjects affected / exposed	38 / 783 (4.85%)	40 / 793 (5.04%)	2 / 49 (4.08%)	4 / 49 (8.16%)
occurrences all number	54	55	2	4
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	27 / 783 (3.45%)	30 / 793 (3.78%)	3 / 49 (6.12%)	1 / 49 (2.04%)
occurrences all number	41	35	3	1
Injection site bruising
subjects affected / exposed	0 / 783 (0.00%)	2 / 793 (0.25%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	0	4	0	2
Non-cardiac chest pain
subjects affected / exposed	2 / 783 (0.26%)	4 / 793 (0.50%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	2	6	0	3
Oedema peripheral
subjects affected / exposed	4 / 783 (0.51%)	6 / 793 (0.76%)	0 / 49 (0.00%)	4 / 49 (8.16%)
occurrences all number	4	7	0	6
Immune system disorders
Seasonal allergy
subjects affected / exposed	13 / 783 (1.66%)	8 / 793 (1.01%)	2 / 49 (4.08%)	0 / 49 (0.00%)
occurrences all number	15	8	2	0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	4 / 783 (0.51%)	8 / 793 (1.01%)	3 / 49 (6.12%)	0 / 49 (0.00%)
occurrences all number	5	8	3	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	12 / 783 (1.53%)	9 / 793 (1.13%)	1 / 49 (2.04%)	2 / 49 (4.08%)
occurrences all number	14	9	1	2
Gastritis
subjects affected / exposed	6 / 783 (0.77%)	7 / 793 (0.88%)	2 / 49 (4.08%)	1 / 49 (2.04%)
occurrences all number	6	8	2	1
Large intestine polyp
subjects affected / exposed	1 / 783 (0.13%)	1 / 793 (0.13%)	2 / 49 (4.08%)	1 / 49 (2.04%)
occurrences all number	1	1	2	1
Nausea
subjects affected / exposed	10 / 783 (1.28%)	5 / 793 (0.63%)	2 / 49 (4.08%)	0 / 49 (0.00%)
occurrences all number	11	13	2	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	62 / 783 (7.92%)	53 / 793 (6.68%)	4 / 49 (8.16%)	7 / 49 (14.29%)
occurrences all number	100	76	4	9
Dyspnoea
subjects affected / exposed	6 / 783 (0.77%)	9 / 793 (1.13%)	3 / 49 (6.12%)	1 / 49 (2.04%)
occurrences all number	6	9	3	1
Nasal congestion
subjects affected / exposed	2 / 783 (0.26%)	12 / 793 (1.51%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	2	12	0	2
Nasal polyps
subjects affected / exposed	5 / 783 (0.64%)	4 / 793 (0.50%)	2 / 49 (4.08%)	2 / 49 (4.08%)
occurrences all number	6	4	2	2
Rhinitis allergic
subjects affected / exposed	38 / 783 (4.85%)	22 / 793 (2.77%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	43	32	0	2
Psychiatric disorders
Insomnia
subjects affected / exposed	12 / 783 (1.53%)	8 / 793 (1.01%)	3 / 49 (6.12%)	0 / 49 (0.00%)
occurrences all number	13	8	3	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	26 / 783 (3.32%)	20 / 793 (2.52%)	5 / 49 (10.20%)	0 / 49 (0.00%)
occurrences all number	32	20	5	0
Back pain
subjects affected / exposed	24 / 783 (3.07%)	21 / 793 (2.65%)	2 / 49 (4.08%)	4 / 49 (8.16%)
occurrences all number	25	21	2	4
Infections and infestations
Bronchitis
subjects affected / exposed	50 / 783 (6.39%)	51 / 793 (6.43%)	3 / 49 (6.12%)	10 / 49 (20.41%)
occurrences all number	66	76	7	16
Upper respiratory tract infection
subjects affected / exposed	61 / 783 (7.79%)	56 / 793 (7.06%)	0 / 49 (0.00%)	7 / 49 (14.29%)
occurrences all number	95	82	0	8
Acute sinusitis
subjects affected / exposed	27 / 783 (3.45%)	44 / 793 (5.55%)	2 / 49 (4.08%)	2 / 49 (4.08%)
occurrences all number	46	61	5	4
Bronchitis bacterial
subjects affected / exposed	19 / 783 (2.43%)	16 / 793 (2.02%)	3 / 49 (6.12%)	2 / 49 (4.08%)
occurrences all number	24	22	3	2
Chronic sinusitis
subjects affected / exposed	12 / 783 (1.53%)	10 / 793 (1.26%)	1 / 49 (2.04%)	2 / 49 (4.08%)
occurrences all number	13	17	1	7
Herpes zoster
subjects affected / exposed	8 / 783 (1.02%)	2 / 793 (0.25%)	2 / 49 (4.08%)	0 / 49 (0.00%)
occurrences all number	8	2	2	0
Oral candidiasis
subjects affected / exposed	14 / 783 (1.79%)	13 / 793 (1.64%)	1 / 49 (2.04%)	2 / 49 (4.08%)
occurrences all number	20	16	1	2
Pharyngitis
subjects affected / exposed	24 / 783 (3.07%)	26 / 793 (3.28%)	0 / 49 (0.00%)	0 / 49 (0.00%)
occurrences all number	28	37	0	0
Respiratory tract infection viral
subjects affected / exposed	8 / 783 (1.02%)	12 / 793 (1.51%)	2 / 49 (4.08%)	0 / 49 (0.00%)
occurrences all number	8	13	2	0
Sinusitis
subjects affected / exposed	22 / 783 (2.81%)	18 / 793 (2.27%)	3 / 49 (6.12%)	4 / 49 (8.16%)
occurrences all number	25	22	3	4
Upper respiratory tract infection bacterial
subjects affected / exposed	15 / 783 (1.92%)	23 / 793 (2.90%)	1 / 49 (2.04%)	2 / 49 (4.08%)
occurrences all number	17	28	1	2
Urinary tract infection
subjects affected / exposed	14 / 783 (1.79%)	8 / 793 (1.01%)	0 / 49 (0.00%)	2 / 49 (4.08%)
occurrences all number	17	8	0	2
Viral upper respiratory tract infection
subjects affected / exposed	124 / 783 (15.84%)	130 / 793 (16.39%)	14 / 49 (28.57%)	13 / 49 (26.53%)
occurrences all number	186	196	22	19

More information

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Were there any global substantial amendments to the protocol? Yes

01 Sep 2015

Update study objectives; Remove requirement of continuing regular study visits after discontinuation of treatment; and other administrative changes.

13 Jan 2016

Add MELTEMI study as an extension of treatment study; Adjust unblinding language.

16 Dec 2016

Add Japanese interim analysis

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Patients in this study had to complete treatment in predecessor studies. Therefore selection bias may exist. Baseline is defined for this study’s entry value, not all values are prior to active treatment due to some patients being treated previously.

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Clinical trials

Clinical Trial Results: A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Basophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Basophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Basophils, Full analysis set, adolescents only

Primary: Change from baseline in Basophils, Full analysis set, adolescents only

Primary: Change from baseline in Leukocytes, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Leukocytes, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Leukocytes, Full analysis set, adolescents only

Primary: Change from baseline in Leukocytes, Full analysis set, adolescents only

Primary: Change from baseline in Lymphocytes, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Lymphocytes, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Lymphocytes, Full analysis set, adolescents only

Primary: Change from baseline in Lymphocytes, Full analysis set, adolescents only

Primary: Change from baseline in Neutrophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Neutrophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Neutrophils, Full analysis set, adolescents only

Primary: Change from baseline in Neutrophils, Full analysis set, adolescents only

Primary: Change from baseline in Eosinophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Eosinophils, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Eosinophils, Full analysis set, adolescents only

Primary: Change from baseline in Eosinophils, Full analysis set, adolescents only

Primary: Change from baseline in ALT, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in ALT, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in ALT, Full analysis set, adolescents only

Primary: Change from baseline in ALT, Full analysis set, adolescents only

Primary: Change from baseline in AST, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in AST, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in AST, Full analysis set, adolescents only

Primary: Change from baseline in AST, Full analysis set, adolescents only

Primary: Change from baseline in Bilirubin, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Bilirubin, Full analysis set, Excluding MELTEMI patients

Primary: Change from baseline in Bilirubin, Full analysis set, adolescents only

Primary: Change from baseline in Bilirubin, Full analysis set, adolescents only

Secondary: Number of overall patients with asthma exacerbations during study period

Secondary: Number of overall patients with asthma exacerbations during study period

Secondary: Number of overall patients with asthma exacerbations during study period, adolescents only

Secondary: Number of overall patients with asthma exacerbations during study period, adolescents only

Secondary: Change from baseline in pre-brochodilator FEV1 (L)

Secondary: Change from baseline in pre-brochodilator FEV1 (L)

Secondary: Change from baseline in pre-brochodilator FEV1 (L), adolescents only

Secondary: Change from baseline in pre-brochodilator FEV1 (L), adolescents only

Secondary: Change from baseline in post-brochodilator FEV1 (L)

Secondary: Change from baseline in post-brochodilator FEV1 (L)

Secondary: Change from baseline in Post-bronchodilator FEV1 (L), adolescents only

Secondary: Change from baseline in Post-bronchodilator FEV1 (L), adolescents only

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, adolescents only

Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, adolescents only

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12)

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12)

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), adolescents only

Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), adolescents only

Secondary: Change of blood eosinophil levels measurement in overall patients

Secondary: Change of blood eosinophil levels measurement in overall patients

Secondary: Change of blood eosinophil levels measurement in adolescents patients.

Secondary: Change of blood eosinophil levels measurement in adolescents patients.

Secondary: Change from baseline in EQ-5D-5L visual analog scale

Secondary: Change from baseline in EQ-5D-5L visual analog scale

Secondary: Change from baseline in EQ-5D-5L visual analog scale, adolescents only

Secondary: Change from baseline in EQ-5D-5L visual analog scale, adolescents only

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI)

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI)

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only

Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), adolescents only

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ)

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ)

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ), adolescents only

Secondary: Classroom productivity loss using Classroom Impairment Questionnaire (CIQ), adolescents only

Secondary: Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI)

Secondary: Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI)

Clinical Trial Results:
A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)