Efficacy and Safety Study of Benralizumab in Patients With Uncontrolled Asthma on Medium to High Dose Inhaled Corticosteroid Plus LABA (MIRACLE)
- Conditions
- Asthma
- Interventions
- Biological: BenralizumabBiological: Placebo
- Registration Number
- NCT03186209
- Lead Sponsor
- AstraZeneca
- Brief Summary
This is a randomised, double-blind, parallel group, placebo-controlled study designed to evaluate the efficacy and safety of a fixed 30 mg dose of benralizumab administered subcutaneously for patients with a history of asthma exacerbations and uncontrolled asthma receiving medium to high-dose inhaled corticosteroid plus long-acting β2-agonist (ICS-LABA) with or without oral corticosteroids and additional asthma controllers.
- Detailed Description
Approximately 666 patients will be randomised. Patients will be stratified by country/region, age group (adult or adolescent), and peripheral blood eosinophil count at time of Visit 1 (\<300 or ≥300 cells/μL).All the patients will be randomised to either placebo or benralizumab (1:1 ratio) for a 48-weeks treatment, every 4 weeks for the first 3 doses and then every 8 weeks thereafter.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 695
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Written informed consent, and assent when applicable for study participation must be obtained prior to any study related procedures being performed (local regulations are to be followed in determining the assent/consent requirements for children and parent[s]/guardian[s]) and according to international guidelines and/or applicable local guidelines.
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Female and male aged 12 to 75 years, inclusively, at the time of Visit 1. For those patients, who are 17 on the day of Visit 1 but will turn 18 after this day, will be considered an adolescent for the purposes of this trial.
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History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (>250μg fluticasone propionate dry powder formulation equivalents total daily dose) and a LABA, for at least 6 months prior to Visit 1.
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Additional maintenance asthma controller medications that are locally approved in a country for the treatment of asthma (e.g., leukotriene receptor antagonists (LTRAs), tiotropium, chromone, theophylline, oral corticosteroid), and have been used for at least 30 days prior to Visit 1 are allowed.
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At least 2 documented asthma exacerbations in the 12 months prior to the date informed consent, and assent when available, during the treatment of medium-to-high dose ICS-LABA that required use of a systemic corticosteroid or a temporary increase from the patient's usual maintenance dose of oral corticosteroid. For patients who are re-screened within 30 days of their screen failure date, the calculation of the 12 month period should be done from the original informed consent, and assent when applicable date.
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Documented post-bronchodilator (post-BD) reversibility in FEV1 of >12% and >200 mL in FEV1 within 12 months prior to Visit 1. If historical documentation is not available, reversibility must be demonstrated and documented at Visit 2.
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Fulfilment of at least 1 of the following conditions over the 7 days prior to randomization:
- >2 days with a daytime or night time symptoms score >1
- Rescue Short-acting β2 agonist (SABA) use on >2 days
- ≥1 nocturnal awakening due to asthma
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Pre-bronchodilator (Pre-BD) FEV1 of <80% predicted (<90% predicted for patients aged 12 to 17 years) at Visit 2.
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ACQ-6 score > = 1.5 at Visit 2.
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Known history of clinically important pulmonary disease other than asthma (e.g., active lung infection, chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (e.g,. allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
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Known history of any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:
- Affect the safety of the patient throughout the study
- Influence the findings of the studies or their interpretations
- Impede the patient's ability to complete the entire duration of study.
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Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent, and assent when applicable, is obtained or during the screening period.
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Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study.
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Current smokers or former smokers with a smoking history of > 10 pack-years.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Benralizumab Benralizumab Benralizumab administered subcutaneously Placebo Placebo Placebo administered subcutaneously
- Primary Outcome Measures
Name Time Method Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma for Baseline Eosinophils >=300/uL From randomization through Study Week 48 Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
- Secondary Outcome Measures
Name Time Method Change From Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Change from baseline at week 48 in evening PEF
Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
Change From Baseline at Week 48 in Total Asthma Rescue Medication Use for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Change from baseline at week 48 in total rescue medication use (number of puffs/day)
Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses.
Change From Baseline at Week 48 in Total Asthma Symptom Score for for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Daytime and nighttime symptoms are reported using a response scale ranging from 0 to 3 where 0 indicates no asthma symptoms. The total asthma symptom score is the sum of the daytime and nighttime scores and ranges from 0 to 6; a decrease in score indicates symptom improvement.
Change From Baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring Rescue Medication for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Change from baseline at Week 48 in proportion of night awakening due to asthma and requiring rescue medication
Time to First Asthma Exacerbation for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Time to first asthma exacerbation over 48-week treatment period
Annual Asthma Exacerbation Rate Associated With an Emergency Room/Urgent Care Visit or a Hospitalization for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization over 48-week treatment period
Number and Percentages of Asthma Specific Health Care Resource Utilization for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Asthma specific health care resource utilization over 48-week treatment period.
The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) Pre-treatment until end of 48-week end of treatment Anti-drug antibodies (ADA) responses at baseline and post baseline.
Change From Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Change from baseline at week 48 in morning PEF
The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration week 0, week 24, week 48 PK trough concentrations at each visit
Percent Change From Baseline at Week 48 in Blood Eosinophil Levels for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Percent change from baseline at Week 48 in blood eosinophil levels
Number and Percentage of Patients With >=1 Asthma Exacerbations Among Patients Who Were on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 Number and percentage of patients with at least one exacerbation over 48-week treatment period
Change From Baseline at Week 48 in Total Score of St. George's Respiratory Questionnaire (SGRQ) for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL From randomization through Study Week 48 The SGRQ is a 50-item PRO instrument developed to measure the HRQoL of patients with airway diseases. The questionnaire is divided into two parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The total score indicates the impact of disease on overall HRQoL. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible HRQoL and 0 indicates the best possible HRQoL.
Trial Locations
- Locations (1)
Research Site
🇨🇳Taoyuan City, Taiwan