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 Overview
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Brief Summary
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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.

Detailed Description
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This study will be conducted at 24 study sites in 3-5 countries. The study duration for each participant will be approximately 52-56 weeks. Approximately 240 participants with severe eosinophilic asthma taking high-dose Inhaled corticosteroids/ long-acting β2-agonist (ICS/LABA) who have been treated for severe eosinophilic asthma with at least 3 consecutive doses of Fasenra® and have clinically responded since the start of Fasenra® treatment (defined for the purpose of this study as an Asthma control questionnaire-5 item (ACQ-5 score) <1.5 at Visit 1 and Visit 2b) will be enrolled into this open-label study. The study consists of a Screening Visit (Visit 1) and 4- to 8-week screening and run-in period (to align the randomisation study visit with the next Fasenra® injection), a reduction period of 32 weeks, and a 16-week maintenance period.

Official Title
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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

Conditions
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Asthma, Severe Eosinophilic Asthma

Intervention / Treatment
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* Drug: Symbicort®
* Drug: Fasenra®
* Drug: Ventolin®


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment reduction arm<br>All participants will receive Fasenra® 30 mg Q8W + SMART or Symbicort® reliever only (starting with medium-dose Symbicort® 200/6 μg ×2 inhalations BID maintenance + Symbicort® 200/6 μg reliever PRN; tapering to Symbicort® 200/6 μg reliever only, as per tapering scheme and depending on degree of asthma control). The reduction period in this arm will last 32 weeks. | Drug: Symbicort®<br>* Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation and Budesonide 200 μg/formoterol fumarate 6 μg per inhalation.<br>* Other names: budesonide/formoterol;Drug: Fasenra®<br>* Participants received Benralizumab 30 mg/mL, 1 mL fill volume via Subcutaneous every 4 weeks for first 3 doses.<br>* Other names: benralizumab;Drug: Ventolin®<br>* Participants received Salbutamol sulfate 100 μg per inhalation as needed.<br>* Other names: salbutamol;|
| Experimental: Reference arm<br>All participants will receive Fasenra® 30 mg Q8W + high-dose Symbicort® maintenance ×2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible participants randomised to the reference arm will continue on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment for 32 weeks. | Drug: Symbicort®<br>* Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation and Budesonide 200 μg/formoterol fumarate 6 μg per inhalation.<br>* Other names: budesonide/formoterol;Drug: Fasenra®<br>* Participants received Benralizumab 30 mg/mL, 1 mL fill volume via Subcutaneous every 4 weeks for first 3 doses.<br>* Other names: benralizumab;Drug: Ventolin®<br>* Participants received Salbutamol sulfate 100 μg per inhalation as needed.<br>* Other names: salbutamol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who reduced their Symbicort® maintenance dose at the end of the reduction period (Week 32) | Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period (Week 32) to: Medium-dose Symbicort® maintenance and reliever therapy (SMART), or Low-dose SMART, or Symbicort® anti-inflammatory reliever only. | At week 32 | 

Secondary Outcome Measures

| Outcome Measure | 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 symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). Mean ACQ-5 is the response, with scores ≤0.75 indicating well controlled, >0.75 and <1.5 indicating partly controlled and ≥1.5 indicating not well controlled asthma. | From week 0 to 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. | To assess changes in patient-reported outcomes for Fasenra®-treated patients while stepping down Symbicort® maintenance treatment. 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). | From week 0 to Week 48 or end of treatment. | 
| Proportion of participants with no deterioration in AQLQ(S)+12 at the end of the reduction period. | To assess changes in patient-reported outcomes for Fasenra®-treated patients while stepping down Symbicort® maintenance treatment. 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). Deterioration defined as a decrease of at least 0.5 units compared to baseline. | At week 32 | 
| Proportion of participants with no deterioration in ACQ-5 at the end of the reduction period. | To assess changes in patient-reported outcomes for Fasenra®-treated patients while stepping down Symbicort® maintenance treatment. Deterioration defined as an increase of at least 0.5 units compared to baseline. | At week 32 | 
| Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period. | To assess the potential for Fasenra®-treated patients to maintain lung function while stepping down Symbicort® maintenance treatment | From week 0 to Week 48 or end of treatment. | 
| Annualised asthma exacerbation rate during the study period. | To assess asthma exacerbation rate. | From Week 0 up to Week 48 | 
| Cumulative total daily inhaled corticosteroids (ICS) dose | To assess the total ICS dose exposure. | From week 0 to Week 48 or end of treatment. | 
| Total daily ICS dose (maintenance + reliever) at the end of the reduction period. | To assess the total ICS dose exposure | At week 32 | 
| 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). | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period. | At Week 32 | 
| Number of exacerbations occurring from end of the reduction period to end of the maintenance period. | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period. | From Week 32 to Week 48 | 
| Total daily ICS dose from the end of the reduction period to the end of the maintenance period. | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period. | From Week 32 to Week 48 | 
| Change in ACQ-5 from the end of the reduction period to the end of the maintenance period. | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period | From Week 32 to Week 48 | 
| Number of participants with adverse Events/Serious Adverse Events. | To assess the safety and tolerability of Fasenra® in patients with severe asthma, while stepping down Symbicort® maintenance treatment and maintaining asthma symptom control | From screening to week 48 or end of treatment | 
| Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period. | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period | From Week 32 to Week 48 | 
| Change in FEV1 from the end of the reduction period to the end of the maintenance period. | To assess if reductions in Symbicort® maintenance achieved at the end of the reduction period are maintained until the end of the maintenance period | From Week 32 to Week 48 | 
| Number and proportion of patients that met each composite endpoint defining clinical remission (no exacerbations, less than 10% deterioration in FEV1, ACQ-5 < 1.5 or ACQ-5 ≤ 0.75) | To assess clinical remission in patients at end of the reduction and maintenance periods | At Week 32 and Week 48 | 
| Number and proportion of patients that met 0, 1, 2, and all 3 composite remission endpoints | To assess clinical remission in patients at end of the reduction and maintenance periods | At Week 32 and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Inflammatory, Reduction period, Inhaled corticosteroids, long-acting β2 agonist