A Study to Assess the Reduction of Daily Maintenance ICS/LABA Treatment Towards Anti-Inflammatory Reliever Treatment in Patients with Severe Eosinophilic Asthma Treated with Benralizumab

Study identifier:D3250C00072

ClinicalTrials.gov identifier:NCT04159519

EudraCT identifier:2019-001924-37

CTIS identifier:N/A

Study Complete

Official Title

SHAMAL: A Multicentre, Randomised, Open-Label, Parallel-Group, Active-Controlled, Phase IV Study to Assess the Reduction of Daily Maintenance ICS/LABA Treatment Towards Anti-Inflammatory Reliever Treatment in Patients with Severe Eosinophilic Asthma Treated with Benralizumab

Medical condition

asthma

Phase

Phase 4

Healthy volunteers

Study drug

Symbicort®, Fasenra®, Ventolin®

Sex

All

Actual Enrollment

170

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 27 Jul 2020

Primary Completion Date: 31 Jan 2023

Study Completion Date: 31 Jan 2023

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1 Provision of informed consent prior to any study-specific procedures.
2 Patient must be aged 18 years old or above at the time of consenting to study participation.
3 Documented current maintenance treatment with high-dose ICS/LABA.
4 ACQ-5 score <1.5 at Visit 1.
5 Treatment with Fasenra® for the indicated diagnosis of severe eosinophilic asthma and has received at least 3 consecutive doses (>8 weeks) prior to Visit 1.
6 Male or female.
7 Negative serum pregnancy test at Visit 1 for women of childbearing potential (WOCBP).
8 WOCBP must agree to use a highly effective method of birth control (confirmed by the Investigator) from randomisation throughout the study duration and within 12 weeks after the last dose of study treatment. Highly effective forms of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include:
• Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation-oral, intravaginal, or transdermal.
• Progestogen-only hormonal contraception associated with inhibition of ovulation-oral, injectable, or implantable.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Bilateral tubal occlusion.
• Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient).
• Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomised partner has received medical assessment of the surgical success).
Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for ≥12 months prior to the planned date of randomisation without an alternative medical cause.
The following age-specific requirements apply:
• Women <50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and have follicle stimulating hormone (FSH) levels in the postmenopausal range. Until FSH is documented to be within menopausal range, treat the patient as WOCBP.
• Women ≥50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
For randomisation at Visit 2b, patients should fulfil the following criteria:
1 ACQ-5 <1.5 at Visit 2b.
2 No increase (worsening) in ACQ-5 of at least ≥0.5 units between Visit 1 and Visit 2b compared to baseline.
3 No asthma exacerbation (see Section 8.1.3) between Visit 1 and Visit 2b.
4 No use of Ventolin® for symptom worsening in >3 out of the 7 days prior to Visit 2b.

Exclusion Criteria

1 As judged by the Investigator, any evidence of a severe or serious treatment-related AE during Fasenra® treatment which in the Investigator’s opinion makes it undesirable for the patient to participate in the study.
2 History of exacerbation requiring systemic corticosteroids or hospitalisation during the last 3 months prior to Visit 1 or during the run-in period.
3 Clinically important pulmonary disease other than asthma (eg, active lung infection, Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis), or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
4 Current smokers or former smokers with a smoking history ≥20 pack/years.
5 History of alcohol or drug abuse within 12 months prior to Visit 1.
6 A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy.
7 History of anaphylaxis to any biologic therapy.
8 Known history of allergy or reaction to any component of the study treatment formulation.
9 A history of known immunodeficiency disorder, including history of a positive human immunodeficiency virus (HIV) test.
10 Current malignancy, or history of malignancy, except for:
• Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.
Prior/Concomitant Therapy
11 Oral corticosteroid use during the last 3 months prior to Visit 1.
12 Receipt of long-acting muscarinic antagonist (LAMAs) or theophyllines from Visit 1 until after Visit 8b, or leukotriene receptor antagonist (LTRAs) from Visit 2b until after Visit 8b.
13 Use of immunosuppressive medication (including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months or 5 half-lives (whichever is longer) prior to the date informed consent is obtained.
14 Receipt of live attenuated vaccines 30 days prior to Visit 1.
15 It is recommended to allow receipt of inactive/killed vaccinations (eg, inactive influenza) provided they are not administered within 1 week before/after any study treatment administration.
16 It is recommended to allow receipt of coronavirus disease 2019 (COVID-19) vaccination prior to study start provided such patients are not randomized until >30 days after last vaccine dose.
17 It is recommended to allow allergen immunotherapy provided it is stable for at least 30 days prior to Visit 1 and there is no anticipated change during the treatment period. Allergen immunotherapy should not be administered on the same day as study visits.
18 Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
19 Five-lipoxygenase inhibitors (eg, zileuton) are prohibited and are not allowed within 30 days of Visit 1 and until after Visit 8b.
20 Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
21 Receipt of systemic treatment with strong CYP3A4 inhibitors (eg, ketoconazole and itraconazole) from Visit 1 until after Visit 8b.
22 Receipt of beta-adrenergic blockers (including eye drops) from Visit 1 until after Visit 8b.
23 Concurrent participation in another clinical study with an Investigational Product or a post-authorisation safety study.
Other Exclusions
24 Planned surgical procedures or other planned life events during the conduct of the study that would affect the patient's ability to comply with study treatment dosing or study assessments.
25 Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site).
26 Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
27 Prior randomisation in the present study.
28 Currently pregnant, breast-feeding, or lactating women.

Location

Research Site

Le Kremlin-Bicêtre, France, 94270

Location

Research Site

Pessac, France, 33600

Location

Research Site

Lyon Cedex 04, France, 69317

Location

Research Site

Dijon Cedex, France, 21079

Location

Research Site

Lille, France, 59000

Location

Research Site

Brest Cedex, France, 29609

Location

Research Site

Roma, Italy, 00168

Location

Research Site

Napoli, Italy, 80131

Arms	Assigned Interventions
Experimental: Treatment reduction arm Participants will receive Benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.	Drug: Symbicort® Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation. Other Name: budesonide/formoterol Drug: Fasenra® Participants will receive Benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 4 weeks for first 3 doses (prior to study inclusion), every 8 weeks thereafter. Other Name: benralizumab Drug: Ventolin® Participants will receive Salbutamol sulfate 100 μg per inhalation as needed. Other Name: salbutamol
Experimental: Reference arm Participants will receive Benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance ×2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible participants randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.	Drug: Symbicort® Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation. Other Name: budesonide/formoterol Drug: Fasenra® Participants will receive Benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 4 weeks for first 3 doses (prior to study inclusion), every 8 weeks thereafter. Other Name: benralizumab Drug: Ventolin® Participants will receive Salbutamol sulfate 100 μg per inhalation as needed. Other Name: salbutamol

Arms

Assigned Interventions

Experimental: Treatment reduction arm
Participants will receive Benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

Drug: Symbicort®
Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation.

Other Name: budesonide/formoterol

Drug: Fasenra®
Participants will receive Benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 4 weeks for first 3 doses (prior to study inclusion), every 8 weeks thereafter.

Other Name: benralizumab

Drug: Ventolin®
Participants will receive Salbutamol sulfate 100 μg per inhalation as needed.

Other Name: salbutamol

Experimental: Reference arm
Participants will receive Benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance ×2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible participants randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Drug: Symbicort®
Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation.

Other Name: budesonide/formoterol

Drug: Fasenra®
Participants will receive Benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 4 weeks for first 3 doses (prior to study inclusion), every 8 weeks thereafter.

Other Name: benralizumab

Drug: Ventolin®
Participants will receive Salbutamol sulfate 100 μg per inhalation as needed.

Other Name: salbutamol

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted between 27 July 2020 and 31 January 2023.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Study began with Screening Visit (Visit 1), followed by 4-8 weeks of screening and run-in. Patients previously exposed to benralizumab and ICS/LABA maintenance treatment prior to study entry received a high dose of Symbicort. At week 0 (Visit 2), 168 patients who met inclusion and randomization criteria were selected to participate in study and received study intervention benralizumab. These patients were randomly assigned to either treatment reduction arm or the reference arm.

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

Study began with Screening Visit (Visit 1), followed by 4-8 weeks of screening and run-in. Patients previously exposed to benralizumab and ICS/LABA maintenance treatment prior to study entry received a high dose of Symbicort. At week 0 (Visit 2), 168 patients who met inclusion and randomization criteria were selected to participate in study and received study intervention benralizumab. These patients were randomly assigned to either treatment reduction arm or the reference arm.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

Reference

Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Participant Flow: Overall Study

	Treatment reduction	Reference
STARTED	125	43
COMPLETED	117	37
NOT COMPLETED	8	6
Adverse Event	1	1
Lack of Efficacy	1	0
Discontinued from study	1	0
Protocol Violation	1	1
Withdrawal by Subject	4	4

Baseline Characteristics

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

The Full Analysis Set (FAS) included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Baseline Measures

	Treatment reduction	Reference	Total
Number of Participants [units: Participants]	125	43	168
Age Continuous [units: Years] Mean ± Standard Deviation	58.1 ± 12.44	56.5 ± 11.70	57.7 ± 12.24
Sex: Female, Male [units: Participants]
Female	69	20	89
Male	56	23	79
Race/Ethnicity, Customized [units: Participants]
White	95	31	126
Asian	0	2	2
Other	2	1	3
Not Reported	5	0	5
Missing	23	9	32
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	8	6	14
Not Hispanic or Latino	91	28	119
Unknown or Not Reported	26	9	35

Outcome Measures

1. Primary Outcome Measure: Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period [ Time Frame: At Week 32 ]

Measure Type	Primary
Measure Name	Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period
Measure Description	Proportion of patients with non-missing Week 32 dose who reduced their Symbicort® maintenance dose at the end of the reduction period (Week 32) to: a) Medium-dose Symbicort® maintenance and reliever therapy (SMART), or b) Low-dose SMART, or c) Symbicort® anti-inflammatory reliever only.
Time Frame	At Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

Description

Treatment reduction

Measured Values

	Treatment reduction
Number of Participants Analyzed [units:participants]	119
Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period [units: Proportion of Participants] Number (95% Confidence Interval)
Medium-dose SMART	0.151 (0.0922 to 0.2285)
Low-dose SMART	0.168 (0.1058 to 0.2476)
Symbicort® reliever-only dose	0.605 (0.5113 to 0.6934)

No statistical analysis provided for Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period

2. Secondary Outcome Measure: Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period [ Time Frame: Week 0 (baseline) and at Week 32 ]

Measure Type	Secondary
Measure Name	Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period
Measure Description	Change from baseline in the ACQ-5 patient reported outcome. This instrument contains 5 asthma symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). The ACQ-5 score is the mean of the responses. Mean scores ≤0.75 indicate well controlled, scores between >0.75 and <1.5 indicate partly controlled, ≥1.5 indicate not well controlled asthma, and individual changes of ≥0.5 are considered to be clinically meaningful. ACQ-5 deterioration is defined as at least a 0.5 unit increase in ACQ-5 score from baseline, and a decrease of at least 0.5 units from baseline indicates improved asthma control.
Time Frame	Week 0 (baseline) and at Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	112	38
Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period [units: Score on a scale] Least Squares Mean (Standard Error)	0.1617 (0.0393)	0.0555 (0.0677)

Statistical Analysis 1 for Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period

Groups^[1]	All groups
Other^[5]	0.1062
95% Confidence Interval	( -0.0485 to 0.2609 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison with reference arm
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period [ Time Frame: Week 0 (baseline) and at Week 32 ]

Measure Type	Secondary
Measure Name	Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period
Measure Description	The AQLQ(S)+12 is a Patient-Reported Outcome (PRO) that measures the health-related quality of life experienced by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Patients are asked to recall their experiences during the previous 2 weeks before each visit and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). Range of Total Score = 0 - 7 as it is an average of responses to the individual questions. High score = better quality of life, and low score = poor quality of life. Change of >0.5 from baseline is considered a meaningful improvement in score.
Time Frame	Week 0 (baseline) and at Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	99	35
Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period [units: Score on a scale] Least Squares Mean (Standard Error)	-0.0279 (0.0559)	0.0064 (0.0950)

Statistical Analysis 1 for Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period

Groups^[1]	All groups
Other^[5]	-0.0343
95% Confidence Interval	( -0.2527 to 0.1841 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison with reference arm
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period [ Time Frame: At Week 32 ]

Measure Type	Secondary
Measure Name	Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period
Measure Description	The AQLQ(S)+12 is a PRO that measures the health-related quality of life experienced by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Patients are asked to recall their experiences during the previous 2 weeks before each visit and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). AQLQ(S)+12 deterioration was defined as at least a 0.5 unit decrease in AQLQ(S)+12 total score from baseline. Patients with no deterioration include patients with improvement or no change.
Time Frame	At Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	43
Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period [units: Participants]
Improvement	12	3
No change	73	28

No statistical analysis provided for Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period

5. Secondary Outcome Measure: Number of patients with no deterioration in ACQ-5 at the end of the reduction period [ Time Frame: At Week 32 ]

Measure Type	Secondary
Measure Name	Number of patients with no deterioration in ACQ-5 at the end of the reduction period
Measure Description	Change from baseline in the ACQ-5 patient reported outcome. This instrument contains 5 asthma symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). The ACQ-5 score is the mean of the responses. Mean scores ≤0.75 indicate well controlled, scores between >0.75 and <1.5 indicate partly controlled, ≥1.5 indicate not well controlled asthma, and individual changes of ≥0.5 are considered to be clinically meaningful. ACQ-5 deterioration is defined as at least a 0.5 units increase in ACQ-5 score from baseline, and a decrease of at least 0.5 units from baseline indicates improved asthma control.
Time Frame	At Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	43
Number of patients with no deterioration in ACQ-5 at the end of the reduction period [units: Participants]
Improvement	6	2
No change	87	28

No statistical analysis provided for Number of patients with no deterioration in ACQ-5 at the end of the reduction period

6. Secondary Outcome Measure: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period [ Time Frame: At Week 0 (baseline), and at Weeks 8, 16, 24, 32, 40, and 48 ]

Measure Type	Secondary
Measure Name	Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period
Measure Description	The potential for benralizumab-treated patients to maintain lung function while stepping down Symbicort® maintenance treatment was assessed. The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters. Change from baseline pre-bronchodilator FEV1 calculated as post-baseline pre-bronchodilator FEV1 (L) minus baseline pre-bronchodilator FEV1 (L) for all post-baseline measurement points.
Time Frame	At Week 0 (baseline), and at Weeks 8, 16, 24, 32, 40, and 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed", and "number analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	43
Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period [units: Liter] Least Squares Mean (Standard Error)
Week 8	0.0411 (0.0183)	0.0549 (0.0315)
Week 16	0.0299 (0.0215)	0.0115 (0.0363)
Week 24	-0.0536 (0.0317)	0.0644 (0.0540)
Week 32	-0.0824 (0.0285)	-0.0016 (0.0482)
Week 40	-0.0953 (0.0280)	0.0428 (0.0476)
Week 48	-0.0889 (0.0272)	0.0059 (0.0475)

No statistical analysis provided for Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period

7. Secondary Outcome Measure: Annualised asthma exacerbation rate during the study period [ Time Frame: From Week 0 up to Week 48 ]

Measure Type	Secondary
Measure Name	Annualised asthma exacerbation rate during the study period
Measure Description	Asthma exacerbation rate was assessed. An asthma exacerbation was defined as a worsening of asthma symptoms that led to any of the following: a) Temporary bolus/burst of systemic corticosteroids (≥3 consecutive days); b) Single depo-injectable dose of corticosteroids (equivalent to a 3-day bolus/burst); c) Visit to emergency room/urgent care (treatment <24 hours) requiring systemic corticosteroids; d) Hospitalization (admission/evaluation ≥24 hours) due to asthma.
Time Frame	From Week 0 up to Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	43
Annualised asthma exacerbation rate during the study period [units: Events/Year] Number (95% Confidence Interval)	0.14 (0.09 to 0.23)	0.14 (0.06 to 0.31)

No statistical analysis provided for Annualised asthma exacerbation rate during the study period

8. Secondary Outcome Measure: Cumulative total daily inhaled corticosteroids (ICS) dose, by period [ Time Frame: Reduction period (From Week 0 up to Week 32); maintenance period (From Week 32 up to Week 48); Study period (Week 0 up to end of maintenance period/ end of study) ]

Measure Type	Secondary
Measure Name	Cumulative total daily inhaled corticosteroids (ICS) dose, by period
Measure Description	The cumulative total daily ICS dose (maintenance +reliever) for: a) reduction period; b) maintenance period; c) study period was assessed.
Time Frame	Reduction period (From Week 0 up to Week 32); maintenance period (From Week 32 up to Week 48); Study period (Week 0 up to end of maintenance period/ end of study)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed", and "number analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	42
Cumulative total daily inhaled corticosteroids (ICS) dose, by period [units: Microgram] Mean (Standard Deviation)
Reduction period	115956.8 (73223.93)	312857.1 (81251.22)
Maintenance period	50984.3 (51148.59)	150400.0 (42180.46)
Study period	157560.0 (114123.69)	448933.3 (131247.22)

No statistical analysis provided for Cumulative total daily inhaled corticosteroids (ICS) dose, by period

9. Secondary Outcome Measure: Total daily ICS dose (maintenance + reliever) at the end of the reduction period [ Time Frame: At Week 32 ]

Measure Type	Secondary
Measure Name	Total daily ICS dose (maintenance + reliever) at the end of the reduction period
Measure Description	The mean total daily ICS dose (maintenance + reliever) during the 8 weeks prior to end of the reduction period was assessed.
Time Frame	At Week 32
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

	Description
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	120	39
Total daily ICS dose (maintenance + reliever) at the end of the reduction period [units: Microgram] Mean (Standard Deviation)	380.028 (440.4995)	1401.796 (316.9718)

No statistical analysis provided for Total daily ICS dose (maintenance + reliever) at the end of the reduction period

10. Secondary Outcome Measure: Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32) [ Time Frame: At Week 48 ]

Measure Type	Secondary
Measure Name	Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32)
Measure Description	Proportion of patients using the same Symbicort daily dose at the end of the maintenance period that they achieved at the end of the reduction period. Proportions were based on patients with non-missing Week 32 and Week 48 Symbicort doses.
Time Frame	At Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Measured Values

	Treatment reduction
Number of Participants Analyzed [units:participants]	118
Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32) [units: Proportion] Number (95% Confidence Interval)	0.958 (0.9039 to 0.9861)

No statistical analysis provided for Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32)

11. Secondary Outcome Measure: Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period [ Time Frame: From Week 32 to Week 48 ]

Measure Type	Secondary
Measure Name	Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period
Measure Description	Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period.
Time Frame	From Week 32 to Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	43
Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period [units: Participants]	5	4

No statistical analysis provided for Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period

12. Secondary Outcome Measure: Total daily ICS dose from the end of the reduction period to the end of the maintenance period [ Time Frame: Week 32, Week 40, and Week 48 ]

Measure Type	Secondary
Measure Name	Total daily ICS dose from the end of the reduction period to the end of the maintenance period
Measure Description	Total daily ICS dose from the end of the reduction period to the end of the maintenance period.
Time Frame	Week 32, Week 40, and Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed", and "number analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	119	38
Total daily ICS dose from the end of the reduction period to the end of the maintenance period [units: Microgram] Mean (Standard Deviation)
Week 32	383.221 (440.9649)	1438.685 (220.6355)
Week 40	408.458 (475.6986)	1424.624 (321.5752)
Week 48	376.356 (449.6614)	1265.356 (472.5244)

No statistical analysis provided for Total daily ICS dose from the end of the reduction period to the end of the maintenance period

13. Secondary Outcome Measure: Change in ACQ-5 from the end of the reduction period to the end of the maintenance period [ Time Frame: From Week 32 to Week 48 ]

Measure Type	Secondary
Measure Name	Change in ACQ-5 from the end of the reduction period to the end of the maintenance period
Measure Description	Change in ACQ-5 score from end of reduction to end of maintenance is reported. This instrument contains 5 asthma symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). The ACQ-5 score is the mean of the responses. Mean scores ≤0.75 indicate well controlled, scores between >0.75 and <1.5 indicate partly controlled, ≥1.5 indicate not well controlled asthma, and individual changes of ≥0.5 are considered to be clinically meaningful. ACQ-5 deterioration is defined as at least a 0.5 unit increase in ACQ-5 score from baseline, and a decrease of at least 0.5 units from baseline indicates improved asthma control.
Time Frame	From Week 32 to Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	110	34
Change in ACQ-5 from the end of the reduction period to the end of the maintenance period [units: Score on a scale] Mean (Standard Deviation)	-0.07 (0.575)	-0.20 (0.814)

No statistical analysis provided for Change in ACQ-5 from the end of the reduction period to the end of the maintenance period

14. Secondary Outcome Measure: Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period [ Time Frame: From Week 32 to Week 48 ]

Measure Type	Secondary
Measure Name	Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period
Measure Description	Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period is reported. The AQLQ(S)+12 is a Patient-Reported Outcome (PRO) that measures the health-related quality of life experienced by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Patients are asked to recall their experiences during the previous 2 weeks before each visit and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). Range of Total Score = 0 - 7 as it is an average of responses to the individual questions. High score = better quality of life, and low score = poor quality of life. Change of >0.5 from baseline is considered a meaningful improvement in score.
Time Frame	From Week 32 to Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	97	31
Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period [units: Score on a scale] Mean (Standard Deviation)	-0.008 (0.4720)	0.060 (0.5658)

No statistical analysis provided for Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period

15. Secondary Outcome Measure: Change in FEV1 from the end of the reduction period to the end of the maintenance period [ Time Frame: From Week 32 to Week 48 ]

Measure Type	Secondary
Measure Name	Change in FEV1 from the end of the reduction period to the end of the maintenance period
Measure Description	The change from the end of the reduction period to the end of the maintenance period for pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) was calculated as Week 48 pre-bronchodilator FEV1 (Liter [L]) minus the maintenance period baseline pre-bronchodilator FEV1 (L). The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters.
Time Frame	From Week 32 to Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	100	30
Change in FEV1 from the end of the reduction period to the end of the maintenance period [units: Liter] Mean (Standard Deviation)	0.0089 (0.2320)	0.0040 (0.2264)

No statistical analysis provided for Change in FEV1 from the end of the reduction period to the end of the maintenance period

16. Secondary Outcome Measure: Number of patients that met each composite endpoint defining clinical remission [ Time Frame: At Week 32 and Week 48 ]

Measure Type	Secondary
Measure Name	Number of patients that met each composite endpoint defining clinical remission
Measure Description	The number of patients meeting each individual component of the composite endpoint defining clinical remission (zero exacerbations, ACQ-5 < 1.5, or ACQ-5 <= 0.75, < 10% FEV1 deterioration) at the end of reduction and maintenance periods were assessed.
Time Frame	At Week 32 and Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" and "number analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	119	38
Number of patients that met each composite endpoint defining clinical remission [units: Participants]
No asthma exacerbation at Week 32	108	37
No asthma exacerbation at Week 48	101	32
ACQ-5 <1.5 at Week 32	106	32
ACQ-5 <1.5 at Week 48	103	32
ACQ-5 ≤ 0.75 at Week 32	65	21
ACQ-5 ≤ 0.75 at Week 48	68	21
FEV1 < 10% decrease from baseline at Week 32	59	26
FEV1 < 10% decrease from baseline at Week 48	66	23

No statistical analysis provided for Number of patients that met each composite endpoint defining clinical remission

17. Secondary Outcome Measure: Number of patients that met 0, 1, 2, and all 3 composite remission endpoints [ Time Frame: At Week 32 and Week 48 ]

Measure Type	Secondary
Measure Name	Number of patients that met 0, 1, 2, and all 3 composite remission endpoints
Measure Description	Clinical remission in patients at end of the reduction and maintenance periods was assessed. A remission score, assigning 1 point for each clinical remission component achieved at week 32 or week 48,was calculated for patients who met 0, 1, 2, and all 3 remission criteria (zero exacerbations,ACQ-5 < 1.5, or ACQ-5 <= 0.75,< 10% FEV1 deterioration). Total remission score ranges from 0 to 3. The higher the score, the more components of remission the patient achieved.
Time Frame	At Week 32 and Week 48
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, overall "number of participants analyzed" and "number analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	89	28
Number of patients that met 0, 1, 2, and all 3 composite remission endpoints [units: Participants]
Remission score (Exacerbation, ACQ-5 ≤ 0.75, FEV1 < 10% decrease from baseline) at Week 32
0
1
2
3
Remission score (Exacerbation, ACQ-5 ≤ 0.75, FEV1 < 10% decrease from baseline) at Week 48
0
1
2
3
Remission score: Exacerbation, ACQ-5 < 1.5, FEV1 < 10% decrease from baseline at Week 32
0
1
2
3
Remission score: Exacerbation, ACQ-5 < 1.5, FEV1 < 10% decrease from baseline at Week 48
0
1
2
3
0	2	0
1	15	5
2	40	8
3	29	15

No statistical analysis provided for Number of patients that met 0, 1, 2, and all 3 composite remission endpoints

18. Secondary Outcome Measure: Number of patients with adverse events or serious adverse events [ Time Frame: From Week 0 (randomization) to Week 48 or end of treatment (total period of study is 2.5 years) ]

Measure Type	Secondary
Measure Name	Number of patients with adverse events or serious adverse events
Measure Description	The safety and tolerability of benralizumab in patients with severe asthma, while stepping down Symbicort® maintenance treatment and maintaining asthma symptom control was assessed.
Time Frame	From Week 0 (randomization) to Week 48 or end of treatment (total period of study is 2.5 years)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set (SAF) included all patients from the FAS who were randomized to the study and received any amount of study treatment during the ICS reduction and maintenance periods and used for all safety analyses. Here, overall "number of participants analyzed" are the patients with available data that were evaluated for this outcome measure within the specified time frame.

Reporting Groups

Description

Treatment reduction

Reference

Measured Values

	Treatment reduction	Reference
Number of Participants Analyzed [units:participants]	125	42
Number of patients with adverse events or serious adverse events [units: Participants]
Any adverse event (AE)	91	35
Any AE with outcome = death	0	0
Any serious adverse event (including events with outcome = death)	12	5
Any AE leading to discontinuation of benralizumab	3	1
Any AE leading to discontinuation of Symbicort	3	1
Any AE leading to discontinuation of Ventolin	2	1
Any AE leading to withdrawal from study	3	1

No statistical analysis provided for Number of patients with adverse events or serious adverse events

Serious Adverse Events

Time Frame	Run-In period: Week -8 to -4 to Week 0 before randomization (total period of 8 weeks); Treatment Period (Treatment reduction and reference): From Week 0 (Randomization) to Week 48 or end of treatment (total period of study is 2.5 years)
Additional Description	The safety analysis set (SAF) included all patients from the FAS who were randomized to the study and received any amount of study treatment during the ICS reduction and maintenance periods and used for all safety analyses. The run-in period includes adverse events occurring during this period reported by the patients in SAF.

Reporting Groups

	Description
Run-In Period	All patients at Screening (Visit 1), switched from their previous ICS/LABA maintenance treatment and rescue medication to high-dose Symbicort maintenance (budesonide/formoterol 400/12 μg) ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever PRN. Patients continued on this medication for the duration of the 4- to 8-week screening and run-in period.
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Serious Adverse Events

Run-In Period

Treatment reduction

Reference

Total, serious adverse events

# participants affected / at risk

1/167 (0.60%)

12/125 (9.60%)

5/42 (11.90%)

Infections and infestations

Helicobacter infection¹

# participants affected / at risk

0/167 (0.00%)

0/125 (0.00%)

1/42 (2.38%)

# events

Infections and infestations

Influenza¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Infections and infestations

Lower respiratory tract infection¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Infections and infestations

Orchitis¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Infections and infestations

Periorbital abscess¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

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

Gallbladder adenocarcinoma¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Immune system disorders

Eosinophilic granulomatosis with polyangiitis¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Metabolism and nutrition disorders

Diabetes mellitus inadequate control¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Nervous system disorders

Seizure¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Cardiac disorders

Atrial flutter¹

# participants affected / at risk

0/167 (0.00%)

0/125 (0.00%)

1/42 (2.38%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹

# participants affected / at risk

0/167 (0.00%)

0/125 (0.00%)

1/42 (2.38%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Gastrointestinal disorders

Inguinal hernia¹

# participants affected / at risk

0/167 (0.00%)

0/125 (0.00%)

1/42 (2.38%)

# events

Reproductive system and breast disorders

Postmenopausal haemorrhage¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Injury, poisoning and procedural complications

Spinal compression fracture¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

0/42 (0.00%)

# events

Injury, poisoning and procedural complications

Vaccination complication¹

# participants affected / at risk

0/167 (0.00%)

0/125 (0.00%)

1/42 (2.38%)

# events

Infections and infestations

Urinary tract infection¹

# participants affected / at risk

1/167 (0.60%)

0/125 (0.00%)

0/42 (0.00%)

# events

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

Other Adverse Events

Time Frame	Run-In period: Week -8 to -4 to Week 0 before randomization (total period of 8 weeks); Treatment Period (Treatment reduction and reference): From Week 0 (Randomization) to Week 48 or end of treatment (total period of study is 2.5 years)
Additional Description	The safety analysis set (SAF) included all patients from the FAS who were randomized to the study and received any amount of study treatment during the ICS reduction and maintenance periods and used for all safety analyses. The run-in period includes adverse events occurring during this period reported by the patients in SAF.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Run-In Period	All patients at Screening (Visit 1), switched from their previous ICS/LABA maintenance treatment and rescue medication to high-dose Symbicort maintenance (budesonide/formoterol 400/12 μg) ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever PRN. Patients continued on this medication for the duration of the 4- to 8-week screening and run-in period.
Treatment reduction	Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
Reference	Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

Other Adverse Events

Run-In Period

Treatment reduction

Reference

Total, other (not including serious) adverse events

# participants affected / at risk

5/167 (2.99%)

46/125 (36.80%)

20/42 (47.62%)

Infections and infestations

Bronchitis¹

# participants affected / at risk

0/167 (0.00%)

7/125 (5.60%)

1/42 (2.38%)

# events

Infections and infestations

COVID-19¹

# participants affected / at risk

2/167 (1.20%)

19/125 (15.20%)

9/42 (21.43%)

# events

Infections and infestations

Nasopharyngitis¹

# participants affected / at risk

3/167 (1.80%)

10/125 (8.00%)

7/42 (16.67%)

# events

Infections and infestations

Rhinitis¹

# participants affected / at risk

0/167 (0.00%)

1/125 (0.80%)

3/42 (7.14%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹

# participants affected / at risk

0/167 (0.00%)

17/125 (13.60%)

4/42 (9.52%)

# events

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

Certain Agreements

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

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

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: This document contains trade secrets and confidential commercial information, disclosure of which is prohibited without providing advance notice to AstraZeneca and opportunity to object.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data

In the CSR synopsis dated 11 September 2023, One patient was erroneously excluded from analysis. Correct count reveals 11 patients in the treatment reduction arm experienced at least one asthma exacerbation during treatment reduction period, resulting in a total of 11 exacerbations. As a consequence, analysis outputs for asthma exacerbation and remission have been affected, for which CSR errata have been submitted along with redaction package.

Results Point of Contact

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

Documents available

Download
CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Dr. David Jackson

Guy’s & St Thomas’ NHS Trust

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSR Synopsis

Trial Results Summaries