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 Aug 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.

No locations available

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

Documents available

CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Investigators

Principal Investigator

Dr. David Jackson

Guy’s & St Thomas’ NHS Trust