Asthma
Conditions
Keywords
Asthma,, Bronchial Diseases,, Respiratory Tract Diseases,, Lung Diseases,, Obstructive Lung Diseases
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.
Interventions
BIOLOGICALBenralizumab
Benralizumab subcutaneously on study week 0 until study week 40 inclusive.
BIOLOGICALPlacebo
Placebo subcutaneously on study week 0 until study week 40 inclusive.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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 8. Pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted (\<90% predicted for patients aged 12 to 17 years) at Visit 2. 9. ACQ-6 score \> = 1.5 at Visit 2.
Exclusion criteria
1. 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). 2. 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. 3. 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. 4. 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. 5. Current smokers or former smokers with a smoking history of \> 10 pack-years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration | week 0, week 24, week 48 | PK trough concentrations at each visit |
| 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. |
| 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 |
| 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 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 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 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 |
| 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 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 |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 48 in Total Asthma Symptom Score 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. |
| Annual Asthma Exacerbation Rate in 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 over the 48-week treatment period among benralizumab and placebo groups |
| 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) |
Countries
China, Philippines, South Korea, Taiwan
Participant flow
Recruitment details
695 participants were randomized to receive treatment in study D3250C00036 (MIRACLE) with Benralizumab or placebo. All the 695 randomized participants received treatment with study drug.
Pre-assignment details
At the first visit, ie, the enrollment visit 1, participants were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrollment, eligible participants were randomized to either placebo or Benralizumab 30 mg at a 1:1 ratio, administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks thereafter.
Participants by arm
| Arm | Count |
|---|---|
| Benralizumab 30 mg Benralizumab administered subcutaneously | 348 |
| Placebo Placebo administered subcutaneously | 347 |
| Total | 695 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Fail to meet randomization criteria | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | PI DECIDED TO DISCONTINUE THE STUDY DUE TO THE LACK OF CRC RESOURCES | 0 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | V18 SKIPPED DUE TO LOGISTICS REASON | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 22 |
Baseline characteristics
| Characteristic | Benralizumab 30 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 11.56 | 51.0 years STANDARD_DEVIATION 12.56 | 51.1 years STANDARD_DEVIATION 12.06 |
| Age, Customized >=12 - <18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized >=18 - <65 years | 299 Participants | 295 Participants | 594 Participants |
| Age, Customized >=65 - <=75 | 48 Participants | 52 Participants | 100 Participants |
| Race/Ethnicity, Customized Asian | 348 Participants | 347 Participants | 695 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 348 Participants | 347 Participants | 695 Participants |
| Sex: Female, Male Female | 221 Participants | 207 Participants | 428 Participants |
| Sex: Female, Male Male | 127 Participants | 140 Participants | 267 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 348 | 0 / 347 |
| other Total, other adverse events | 194 / 348 | 194 / 347 |
| serious Total, serious adverse events | 44 / 348 | 63 / 347 |
Outcome results
Primary
Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma for Baseline Eosinophils >=300/uL
Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma for Baseline Eosinophils >=300/uL | 0.49 events/patient-year |
| Placebo | Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma for Baseline Eosinophils >=300/uL | 1.88 events/patient-year |
p-value: <0.000195% CI: [0.19, 0.36]Negative binomial
Secondary
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
Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization over 48-week treatment period
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | 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 | 0.06 events/patient-year |
| Placebo | 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 | 0.14 events/patient-year |
p-value: 0.022295% CI: [0.24, 0.9]Negative binomial
Secondary
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
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.
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -1.22 Scores on a scale | Standard Deviation 0.901 |
| Placebo | 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 | -0.79 Scores on a scale | Standard Deviation 0.962 |
p-value: <0.000195% CI: [-0.58, -0.28]Mixed Models Analysis
Secondary
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
Change from baseline at week 48 in evening PEF
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | 45.661 L/min | Standard Deviation 85.4642 |
| Placebo | 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 | 7.989 L/min | Standard Deviation 68.0632 |
p-value: <0.000195% CI: [21.52, 50.18]Mixed Models Analysis
Secondary
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
Change from baseline at week 48 in morning PEF
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | 54.194 L/min | Standard Deviation 86.3963 |
| Placebo | 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 | 12.995 L/min | Standard Deviation 68.7947 |
p-value: <0.000195% CI: [24.24, 53.07]Mixed Models Analysis
Secondary
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
Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | 0.333 Liter | Standard Deviation 0.4499 |
| Placebo | 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 | 0.103 Liter | Standard Deviation 0.4841 |
p-value: <0.000195% CI: [0.17, 0.34]Mixed Models Analysis
Secondary
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
Change from baseline at Week 48 in proportion of night awakening due to asthma and requiring rescue medication
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -0.15 Proportion of nights | Standard Deviation 0.22 |
| Placebo | 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 | -0.15 Proportion of nights | Standard Deviation 0.26 |
p-value: 0.338595% CI: [-0.03, 0.01]Mixed Models Analysis
Secondary
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
Change from baseline at week 48 in total rescue medication use (number of puffs/day)
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -0.85 Puffs/day | Standard Deviation 1.865 |
| Placebo | 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 | -0.89 Puffs/day | Standard Deviation 2.213 |
p-value: 0.183595% CI: [-0.42, 0.08]Mixed Models Analysis
Secondary
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
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.
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -1.07 Scores on a scale | Standard Deviation 1.126 |
| Placebo | 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 | -0.80 Scores on a scale | Standard Deviation 1.129 |
p-value: 0.012695% CI: [-0.45, -0.05]Mixed Models Analysis
Secondary
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
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.
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -23.24 Scores on a scale | Standard Deviation 20.509 |
| Placebo | 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 | -14.75 Scores on a scale | Standard Deviation 21.838 |
p-value: <0.000195% CI: [-12.79, -5.6]Mixed Models Analysis
Secondary
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
Number and percentage of patients with at least one exacerbation over 48-week treatment period
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Benralizumab 30 mg | 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 | 55 Participants |
| Placebo | 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 | 125 Participants |
p-value: <0.000195% CI: [0.19, 0.42]Cochran-Mantel-Haenszel
Secondary
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
Asthma specific health care resource utilization over 48-week treatment period.
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg | 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 | Unscheduled Outpatient Visits | 53 Participants |
| Benralizumab 30 mg | 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 | Telephone Calls | 35 Participants |
| Benralizumab 30 mg | 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 | Emergency Department Visits | 11 Participants |
| Benralizumab 30 mg | 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 | Ambulance Transports | 2 Participants |
| Benralizumab 30 mg | 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 | Home Visits | 1 Participants |
| Benralizumab 30 mg | 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 | Advanced Pulmonary Function Test | 4 Participants |
| Benralizumab 30 mg | 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 | Hospitalisations | 6 Participants |
| Placebo | 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 | Advanced Pulmonary Function Test | 8 Participants |
| Placebo | 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 | Hospitalisations | 21 Participants |
| Placebo | 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 | Emergency Department Visits | 12 Participants |
| Placebo | 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 | Unscheduled Outpatient Visits | 99 Participants |
| Placebo | 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 | Home Visits | 2 Participants |
| Placebo | 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 | Telephone Calls | 71 Participants |
| Placebo | 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 | Ambulance Transports | 2 Participants |
Secondary
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
Percent change from baseline at Week 48 in blood eosinophil levels
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | -80.6 Percent change | Standard Deviation 34.65 |
| Placebo | 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 | 42.3 Percent change | Standard Deviation 380.86 |
p-value: <0.000195% CI: [-169.78, -68.84]Mixed Models Analysis
Secondary
The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs)
Anti-drug antibodies (ADA) responses at baseline and post baseline.
Time frame: Pre-treatment until end of 48-week end of treatment
Population: Safety analysis set; number analyzed includes participants with available value at each specified time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at any time, including baseline and/or post-baseline (ADA prevalence) | 58 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-emergent ADA positive, including treatment-induced and treatment-boosted ADA positive | 58 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-induced ADA positive | 56 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-boosted ADA positive | 2 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at both baseline and at least one post-baseline assessment | 2 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at baseline only | 0 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA persistently positive | 40 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA transiently positive | 16 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive with maximum titre > median of maximum titres | 25 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive with maximum titre <= median of maximum titres | 33 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | nAb prevalence (nAb positive at any time, including baseline and/or post-baseline) | 55 Participants |
| Benralizumab 30 mg | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | nAb incidence | 55 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | nAb prevalence (nAb positive at any time, including baseline and/or post-baseline) | 1 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at any time, including baseline and/or post-baseline (ADA prevalence) | 6 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA persistently positive | 1 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-emergent ADA positive, including treatment-induced and treatment-boosted ADA positive | 2 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive with maximum titre <= median of maximum titres | 4 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-induced ADA positive | 2 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA transiently positive | 1 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | Treatment-boosted ADA positive | 0 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | nAb incidence | 1 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at both baseline and at least one post-baseline assessment | 2 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive with maximum titre > median of maximum titres | 2 Participants |
| Placebo | The Immunogenicity of Benralizumab as Assessed by the Presence of Anti-drug Antibodies (ADAs) | ADA positive at baseline only | 2 Participants |
Secondary
The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration
PK trough concentrations at each visit
Time frame: week 0, week 24, week 48
Population: PK analysis set; number analyzed includes participants with available value at each specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg | The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration | Week 0 | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Benralizumab 30 mg | The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration | Week 24 | 137.914 ng/mL | Geometric Coefficient of Variation 432.419 |
| Benralizumab 30 mg | The Pharmacokinetics (PK) of Benralizumab as Assessed by Trough Concentration | Week 48 | 123.476 ng/mL | Geometric Coefficient of Variation 395.951 |
Secondary
Time to First Asthma Exacerbation for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL
Time to first asthma exacerbation over 48-week treatment period
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \>=300/uL
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg | Time to First Asthma Exacerbation for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL | NA Days |
| Placebo | Time to First Asthma Exacerbation for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils >=300/uL | 227 Days |
p-value: <0.000195% CI: [0.23, 0.43]Regression, Cox
Other Pre-specified
Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL
Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
Time frame: From randomization through Study Week 48.
Population: Full analysis set, Baseline eosinophils \<300/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL | 0.72 events/patient-year |
| Placebo | Annual Asthma Exacerbation Rate in Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL | 0.87 events/patient-year |
p-value: 0.451995% CI: [0.51, 1.35]Negative binomial
Other Pre-specified
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
Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \<300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | 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 | 0.178 Liter | Standard Deviation 0.4068 |
| Placebo | 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 | 0.045 Liter | Standard Deviation 0.3626 |
p-value: 0.021495% CI: [0.02, 0.22]Mixed Models Analysis
Other Pre-specified
Change From Baseline at Week 48 in Total Asthma Symptom Score for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL
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.
Time frame: From randomization through Study Week 48
Population: Full analysis set, Baseline eosinophils \<300/uL; number analyzed refers to records with value available at Week 48 for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Change From Baseline at Week 48 in Total Asthma Symptom Score for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL | -0.97 Scores on a scale | Standard Deviation 1.26 |
| Placebo | Change From Baseline at Week 48 in Total Asthma Symptom Score for Patients on Medium to High-dose ICS-LABA With Uncontrolled Asthma and Baseline Eosinophils <300/uL | -0.75 Scores on a scale | Standard Deviation 1.105 |
p-value: 0.158995% CI: [-0.51, 0.08]Mixed Models Analysis