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

NCT04159519 | Completed Phase 4 Results

• 2 other identifiers: D3250C000722019-001924-37
• Study Type: interventional
• Target: 170
• Locations: 4 countries
• Sites: 23

Brief Summary

This is a multicentre, randomised, open-label, parallel-group, active-controlled, phase IV study to assess the reduction of daily Symbicort® maintenance to anti-inflammatory reliever treatment only in participants with severe eosinophilic asthma on Fasenra® treatment, while maintaining asthma control.

Conditions

Asthma; Severe Eosinophilic Asthma

Keywords

Anti-Inflammatory; Reduction period; Inhaled corticosteroids; long-acting β2 agonist

Outcome Measures

Primary Outcomes (1)

• 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 (17)

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

  Week 0 (baseline) and at Week 32

• 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

  Week 0 (baseline) and at Week 32

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

  At Week 32

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

  At Week 32

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

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

Study Arms (2)

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

Symbicort® DRUG

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

Also known as: budesonide/formoterol

Reference arm; Treatment reduction arm

Fasenra® DRUG

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.

Also known as: benralizumab

Reference arm; Treatment reduction arm

Ventolin® DRUG

Participants will receive Salbutamol sulfate 100 μg per inhalation as needed.

Also known as: salbutamol

Reference arm; Treatment reduction arm

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (23)

Research Site

Brest, 29609, France

Location

Research Site

Dijon, 21079, France

Location

Research Site

Le Kremlin-Bicêtre, 94270, France

Location

Research Site

Lille, 59000, France

Location

Research Site

Lyon, 69317, France

Location

Research Site

Pessac, 33600, France

Location

Research Site

Berlin, 10969, Germany

Location

Research Site

Bonn, 53105, Germany

Location

Research Site

Cottbus, 03050, Germany

Location

Research Site

Hamburg, 20354, Germany

Location

Research Site

Hamburg, 22767, Germany

Location

Research Site

Hanover, 30625, Germany

Location

Research Site

Jena, 7740, Germany

Location

Research Site

Mainz, 55131, Germany

Location

Research Site

Marburg, 35043, Germany

Location

Research Site

München, 81377, Germany

Location

Research Site

Bergamo, 24127, Italy

Location

Research Site

Napoli, 80131, Italy

Location

Research Site

Roma, 00168, Italy

Location

Research Site

Belfast, BT9 7BL, United Kingdom

Location

Research Site

Cambridge, CB2 2QQ, United Kingdom

Location

Research Site

London, SE1 9RT, United Kingdom

Location

Research Site

Nottingham, NG15 1PB, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 38071986 DERIVED

• Butler CA, Heaney LG. Fractional exhaled nitric oxide and asthma treatment adherence. Curr Opin Allergy Clin Immunol. 2021 Feb 1;21(1):59-64. doi: 10.1097/ACI.0000000000000704.

  PMID: 33369570 DERIVED

Related Links

• CSR Synopsis

MeSH Terms

Conditions

Asthma; Pulmonary Eosinophilia

Interventions

Budesonide, Formoterol Fumarate Drug Combination; benralizumab; Albuterol

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hypereosinophilic Syndrome; Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Formoterol Fumarate; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Budesonide; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Phenethylamines; Ethylamines

Limitations and Caveats

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

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Dr. David Jackson

  Guy's & St Thomas' NHS Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2019
• First Posted: November 12, 2019
• Study Start: July 27, 2020
• Primary Completion: January 31, 2023
• Study Completion: January 31, 2023
• Last Updated: January 9, 2025
• Results First Posted: January 9, 2025

Record last verified: 2024-11

Locations

DE (10); IT (3); GB (4); FR (6)