A Study to Assess the Reduction of Daily Maintenance ICS/... | NCT04159519

NCT04159519

ID	Type	Description	Link
2019-001924-37	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Treatment reduction arm	Experimental	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® Drug: Fasenra® Drug: Ventolin®
Reference arm	Experimental	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® Drug: Fasenra® Drug: Ventolin®

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Symbicort®	Drug	Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation.	Reference arm

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Proportion of Patients Who Reduced Their Symbicort® Maintenance Dose at the End of the Reduction Period	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.	At Week 32

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Asthma Control Questionnaire-5 Item (ACQ-5) Score at the End of the Reduction Period	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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of informed consent prior to any study-specific procedures.
Patient must be aged 18 years old or above at the time of consenting to study participation.
Documented current maintenance treatment with high-dose ICS/LABA.
ACQ-5 score <1.5 at Visit 1.
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.
Male or female.
Negative serum pregnancy test at Visit 1 for women of childbearing potential (WOCBP).
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:

ACQ-5 <1.5 at Visit 2b.
No increase (worsening) in ACQ-5 of at least ≥0.5 units between Visit 1 and Visit 2b compared to baseline.
No asthma exacerbation (see Section 8.1.3) between Visit 1 and Visit 2b.
No use of Ventolin® for symptom worsening in >3 out of the 7 days prior to Visit 2b.

Exclusion Criteria:

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.
History of exacerbation requiring systemic corticosteroids or hospitalisation during the last 3 months prior to Visit 1 or during the run-in period.
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).
Current smokers or former smokers with a smoking history ≥20 pack/years.
History of alcohol or drug abuse within 12 months prior to Visit 1.
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.
History of anaphylaxis to any biologic therapy.
Known history of allergy or reaction to any component of the study treatment formulation.
A history of known immunodeficiency disorder, including history of a positive human immunodeficiency virus (HIV) test.
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
Oral corticosteroid use during the last 3 months prior to Visit 1.
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.
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.
Receipt of live attenuated vaccines 30 days prior to Visit 1.
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.
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.
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.
Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
Five-lipoxygenase inhibitors (eg, zileuton) are prohibited and are not allowed within 30 days of Visit 1 and until after Visit 8b.
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.
Receipt of systemic treatment with strong CYP3A4 inhibitors (eg, ketoconazole and itraconazole) from Visit 1 until after Visit 8b.
Receipt of beta-adrenergic blockers (including eye drops) from Visit 1 until after Visit 8b.
Concurrent participation in another clinical study with an Investigational Product or a post-authorisation safety study.

Other Exclusions
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.
Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site).
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.
Prior randomisation in the present study.
Currently pregnant, breast-feeding, or lactating women.

Contacts/Locations Module

Name	Affiliation	Role
Dr. David Jackson	Guy's & St Thomas' NHS Trust	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Brest		29609	France
Research Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
38071986	Derived	Jackson DJ, Heaney LG, Humbert M, Kent BD, Shavit A, Hiljemark L, Olinger L, Cohen D, Menzies-Gow A, Korn S; SHAMAL Investigators. Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study. Lancet. 2024 Jan 20;403(10423):271-281. doi: 10.1016/S0140-6736(23)02284-5. Epub 2023 Dec 7.
33369570

Label	URL
CSR Synopsis	View source

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 15, 2022	Nov 26, 2024

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Treatment reduction arm

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

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00058.1± 12.44 BG00156.5± 11.70 BG00257.7± 12.24

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00069 BG00120 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0008 BG0016 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
White	BG00095 BG00131 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Proportion of Patients Who Reduced Their Symbicort® Maintenance Dose at the End of the Reduction Period

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.

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.

Posted

Number

95% Confidence Interval

Proportion of Participants

At Week 32

ID	Title	Description
OG000	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.

Units	Counts
Participants	OG000119

Title

Denominators

Categories

Medium-dose SMART

Title	Measurements
	OG0000.151(0.0922 to 0.2285)

Low-dose SMART

Title	Measurements
	OG0000.168(0.1058 to 0.2476)

Symbicort® reliever-only dose

Secondary

Change From Baseline in Asthma Control Questionnaire-5 Item (ACQ-5) Score at the End of the Reduction Period

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.

Posted

Least Squares Mean

Standard Error

Score on a scale

Week 0 (baseline) and at Week 32

ID	Title	Description
OG000	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.

Secondary

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

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.

Posted

Least Squares Mean

Standard Error

Score on a scale

Week 0 (baseline) and at Week 32

ID	Title	Description
OG000	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.

Secondary

Number of Patients With no Deterioration in AQLQ(S)+12 at the End of the Reduction Period

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.

The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Posted

Count of Participants

Participants

At Week 32

ID	Title	Description
OG000	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.
OG001	Reference

Secondary

Number of Patients With no Deterioration in ACQ-5 at the End of the Reduction Period

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.

The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Posted

Count of Participants

Participants

At Week 32

ID	Title	Description
OG000	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.
OG001	Reference

Secondary

Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) During the Study Period

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.

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.

Posted

Least Squares Mean

Standard Error

Liter

At Week 0 (baseline), and at Weeks 8, 16, 24, 32, 40, and 48

ID	Title	Description
OG000	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.

Secondary

Annualised Asthma Exacerbation Rate During the Study Period

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.

The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Posted

Number

95% Confidence Interval

Events/Year

From Week 0 up to Week 48

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Cumulative Total Daily Inhaled Corticosteroids (ICS) Dose, by Period

The cumulative total daily ICS dose (maintenance +reliever) for: a) reduction period; b) maintenance period; c) study period was assessed.

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.

Posted

Mean

Standard Deviation

Microgram

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)

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Total Daily ICS Dose (Maintenance + Reliever) at the End of the Reduction Period

The mean total daily ICS dose (maintenance + reliever) during the 8 weeks prior to end of the reduction period was assessed.

Posted

Mean

Standard Deviation

Microgram

At Week 32

ID	Title	Description
OG000	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.
OG001	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.

Secondary

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)

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.

Posted

Number

95% Confidence Interval

Proportion

At Week 48

ID	Title	Description
OG000	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.

Units	Counts

Secondary

Number of Patients With at Least 1 Exacerbation Occurring From End of the Reduction Period to End of the Maintenance Period

Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period.

The FAS included all randomised patients, irrespective of their protocol adherence and continued participation in the study.

Posted

Count of Participants

Participants

From Week 32 to Week 48

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Total Daily ICS Dose From the End of the Reduction Period to the End of the Maintenance Period

Total daily ICS dose from the end of the reduction period to the end of the maintenance period.

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.

Posted

Mean

Standard Deviation

Microgram

Week 32, Week 40, and Week 48

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Change in ACQ-5 From the End of the Reduction Period to the End of the Maintenance Period

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.

Posted

Mean

Standard Deviation

Score on a scale

From Week 32 to Week 48

ID	Title	Description
OG000	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.

Secondary

Change in AQLQ(S)+12 From the End of the Reduction Period to the End of the Maintenance Period

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.

Posted

Mean

Standard Deviation

Score on a scale

From Week 32 to Week 48

ID	Title	Description
OG000	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.

Secondary

Change in FEV1 From the End of the Reduction Period to the End of the Maintenance Period

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.

Posted

Mean

Standard Deviation

Liter

From Week 32 to Week 48

ID	Title	Description
OG000	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.
OG001	Reference

Secondary

Number of Patients That Met Each Composite Endpoint Defining Clinical Remission

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.

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.

Posted

Count of Participants

Participants

At Week 32 and Week 48

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Number of Patients That Met 0, 1, 2, and All 3 Composite Remission Endpoints

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.

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.

Posted

Count of Participants

Participants

At Week 32 and Week 48

ID	Title	Description
OG000	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.
OG001	Reference

Secondary

Number of Patients With Adverse Events or Serious Adverse Events

The safety and tolerability of benralizumab in patients with severe asthma, while stepping down Symbicort® maintenance treatment and maintaining asthma symptom control was assessed.

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.

Posted

Count of Participants

Participants

From Week 0 (randomization) to Week 48 or end of treatment (total period of study is 2.5 years)

ID	Title	Description
OG000	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.
OG001	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.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.	167	1	167	5	167
EG001	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.	125	12	125	46	125
EG002	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.	42	5	42	20	42

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Helicobacter infection	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0010 events0 affected125 at risk EG0021 events1 affected42 at risk
Influenza	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Orchitis	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Periorbital abscess	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Gallbladder adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Eosinophilic granulomatosis with polyangiitis	Immune system disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Seizure	Nervous system disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Atrial flutter	Cardiac disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0010 events0 affected125 at risk EG0021 events1 affected42 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0010 events0 affected125 at risk EG0021 events1 affected42 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Inguinal hernia	Gastrointestinal disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0010 events0 affected125 at risk EG0021 events1 affected42 at risk
Postmenopausal haemorrhage	Reproductive system and breast disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Ankle fracture	Injury, poisoning and procedural complications	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0020 events0 affected42 at risk
Vaccination complication	Injury, poisoning and procedural complications	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0010 events0 affected125 at risk EG0021 events1 affected42 at risk
Urinary tract infection	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0001 events1 affected167 at risk EG0010 events0 affected125 at risk EG0020 events0 affected42 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bronchitis	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0018 events7 affected125 at risk EG0021 events1 affected42 at risk
COVID-19	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0002 events2 affected167 at risk EG00119 events19 affected125 at risk EG0029 events9 affected42 at risk
Nasopharyngitis	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0003 events3 affected167 at risk EG00112 events10 affected125 at risk EG0028 events7 affected42 at risk
Rhinitis	Infections and infestations	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG0011 events1 affected125 at risk EG0024 events3 affected42 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA version 25.1	Non-systematic Assessment	EG0000 events0 affected167 at risk EG00120 events17 affected125 at risk EG0024 events4 affected42 at risk

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.

Certain Agreements

ID	Term
D001249	Asthma
D011657	Pulmonary Eosinophilia

Ancestor Terms

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases
D017681	Hypereosinophilic Syndrome
D004802	Eosinophilia
D007960	Leukocyte Disorders
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases

ID	Term
D000069502	Budesonide, Formoterol Fumarate Drug Combination
C571386	benralizumab
D000420	Albuterol

Ancestor Terms

ID	Term
D000068759	Formoterol Fumarate
D004983	Ethanolamines
D000605	Amino Alcohols
D000438	Alcohols
D009930	Organic Chemicals
D000588	Amines
D019819	Budesonide
D011282	Pregnenediones
D011283	Pregnenes
D011278	Pregnanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D004338	Drug Combinations
D004364	Pharmaceutical Preparations
D010627	Phenethylamines
D005021	Ethylamines

Units	Counts
Participants	OG000125 OG00143

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.