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Completed

NCT Number: NCT04159519

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

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.

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Key information

Conditions

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

Age range

18 year–130 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Research Site, Brest, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Symbicort®

Drug

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

Other names: budesonide/formoterol

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.

Other names: benralizumab

Ventolin®

Drug

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

Other names: salbutamol

Primary outcomes

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

    Time frame: At Week 32

    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.

Secondary outcomes

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

    Time frame: Week 0 (baseline) and at Week 32

    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.

  2. Change From Baseline in Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) at the End of the Reduction Period

    Time frame: Week 0 (baseline) and at Week 32

    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.

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

    Time frame: At Week 32

    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.

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

    Time frame: At Week 32

    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.

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

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

    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.

  6. Annualised Asthma Exacerbation Rate During the Study Period

    Time frame: From Week 0 up to Week 48

    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.

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

    Time frame: Reduction period (From Week 0 up to Week 32); maintenance period (From Week 32 up to Week 48); Study period (Week 0 up to end of maintenance period/ end of study)

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

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

    Time frame: At Week 32

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

  9. Proportion of Participants Using the Same Symbicort® Daily Dose at the End of the Maintenance Period (Week 48) That They Achieved at the End of the Reduction Period (Week 32)

    Time frame: At Week 48

    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.

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

    Time frame: From Week 32 to Week 48

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

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

    Time frame: Week 32, Week 40, and Week 48

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

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

    Time frame: From Week 32 to Week 48

    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.

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

    Time frame: From Week 32 to Week 48

    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.

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

    Time frame: From Week 32 to Week 48

    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.

  15. Number of Patients That Met Each Composite Endpoint Defining Clinical Remission

    Time frame: At Week 32 and Week 48

    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.

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

    Time frame: At Week 32 and Week 48

    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.

  17. Number of Patients With Adverse Events or Serious Adverse Events

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

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

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Registry information

Official study 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

Important dates

Study start
2020
Primary completion
2023
Study completion
2023
First posted
Nov 12, 2019
Registry last updated
Jan 9, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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