Asthma
Conditions
Keywords
Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases, OCS, Oral Corticosteroids
Brief summary
The purpose of this trial is to confirm if benralizumab can reduce the use of maintenance OCS in systemic corticosteroid dependent patients with severe refractory asthma with elevated eosinophils.
Interventions
BIOLOGICALBenralizumab
Benralizumab administered subcutaneously every 4 weeks
BIOLOGICALPlacebo
Placebo subcutaneously on study week 0 until study week 24 inclusive.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. Female and male aged from 18 to 75 years, inclusively. 3. History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA. 4. Elevated level of peripheral blood eosinophil 5. Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1 6. Chronic oral corticosteroid therapy for at least 6 continuous months directly preceding Visit 1. Subjects must be on doses equivalent to 7.5 - 40 mg/day of prednisolone/prednisone at Visit 1 and be on a stable dose for at least 2 weeks prior to randomization. Patients must agree to switch to study required prednisone/prednisolone as their oral corticosteroid for the duration of the study. 7. Patients with documented failures of OCS reduction within 6 months prior to Visit 1 will not be required to proceed through the dose optimization phase during run-in. 8. Morning pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted 9. Evidence of asthma as documented by either: Airway reversibility (FEV1 ≥12% and 200 mL) demonstrated at Visit 1, Visit 2, or Visit 3 using the Maximum Post-bronchodilator Procedure OR Documented reversibility in the previous 24 months prior to Visit 1 OR Airway hyperresponsiveness (PC20 FEV1 methacholine concentration ≤8mg/mL) documented in the previous 12 months prior to planned date of randomization OR Airflow variability in clinic FEV1 ≥20% between 2 consecutive clinic visits documented in the 12 months prior to the planned date of randomization (FEV1 recorded during an exacerbation should not be considered for this criterion). All patients must have reversibility testing performed before randomization to establish a baseline characteristic. If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomization, the site should reiterate the need to withhold short- and long-acting bronchodilators prior to Visit 3 in an effort to meet this inclusion criterion. 10. At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained 11. Optimized OCS dose reached at least 2 weeks prior to randomization 12. Additional asthma controller medication must not have been initiated during run in/optimization period (not applicable for management of exacerbations during screening/ run in optimization phase) 13. At least 70% compliance with OCS use 14. At least 70% compliance with usual asthma controller ICS-LABA 15. Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary)
Exclusion criteria
1. Clinically important pulmonary disease other than asthma or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts. 2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 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 is obtained or during the screening/run-in period 4. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during run-in/optimization 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. History of life-threatening asthma 6. Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase 7. Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5 8. Receipt of oral corticosteroids, other than prednisone or prednisolone, as the maintenance oral steroid controller for asthma symptoms from Visit 1 and throughout the study. 9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control | Week 28 | Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL | Week 28 | Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
| The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | Week 28 | Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
| The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | Week 28 | Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
| The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control. | Week 28 | Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
| The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control | Week 28 | Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event. |
| Number and Percentage of Patients With ≥1 Asthma Exacerbation | Immediately following the randomisation through Study Week 28 | Number and percentage of patients with at least one post randomisation asthma exacerbation. |
| Time to the First Asthma Exacerbation | The time from randomisation to the date of first asthma exacerbation over 28 weeks | Time to the first occurrence of asthma exacerbation post randomisation |
| Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit | The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks. | Time to the first exacerbation requiring hospitalization or ER visit post randomisation |
| The Annualized Rate of Asthma Exacerbation | The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up | The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up. |
| The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization | The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up | The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator that are associated with an emergency room visit or a hospitalization adjusted by the time of follow-up. |
| Number of Days in Hospital Due to Asthma | The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up | Number of days in hospital due to asthma, if none, 0 day is considered |
| Change From Baseline to Week 28 in Pre-bronchodilator FEV1 | Change from baseline at week 28 | Baseline is defined as the last non-missing value prior to the first dose of study treatment. Change from baseline to Week 28 in two treatment groups is compared to placebo group. |
| Change From Baseline to Week 28 in Asthma Symptom Scores (Total) | Change from baseline at week 28 | Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better. |
| Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime) | Change from baseline at week 28 | Asthma symptoms during daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better. |
| Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime) | Change from baseline at week 28 | Asthma symptoms during night time are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better. |
| Change From Baseline to Week 28 in Rescue Medication Use | Change from baseline at week 28 | Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this will be considered as missing. The number of inhalations (puffs) per day will be calculated as follows: Number of night inhaler puffs + 2 x \[number of night nebulizer times\] + number of day inhaler puffs + 2 x \[number of day nebulizer times\]. |
| Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | Week 28 | Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose. |
| Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow) | Change from baseline at week 28 | Evening peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data |
| Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication | Change from baseline at week 28 | Baseline is defined as the proportion of nights from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly proportions based on daily diary data. If more than 50% of data are missing in a 14 day period then this will be considered as missing.Proportion of nights with noctural awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data. |
| Change From Baseline to Week 28 in ACQ-6 | Change from baseline at week 28 | 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. Mean scores of \<=0.75 indicates well-controlled asthma, scores between 0.75 to \<=1.5 indicate partly controlled asthma, and \>1.5 indicates not well controlled asthma. |
| ACQ-6 Responders (Improvement) at Week 28 | Week 28 | Improvement is defined as ACQ-6 (End of treatment - baseline) \<= -0.5. No change is defined as ACQ-6 (End of treatment - baseline) \>-0.5 and \<0.5. Deterioration is defined as ACQ-6 (End of treatment - baseline) \>= 0.5. ACQ-6 score is defined as the average of the first 6 items of the ACQ questionnaire on symptoms, activity limitations and rescue medication.Scores range from 0 (totally controlled) to 6 (severely uncontrolled). Baseline is defined as the last non-missing value prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable ACQ-6 at week 28 are considered non-responder. |
| Change From Baseline at Week 28 in AQLQ(S)+12 (Overall) | Change from baseline at week 28 | AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of \>=0.5 are considered clinically meaningful. |
| AQLQ(s)+12 Responders (Improvement) at Week 28 | Week 28 | AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. Improvement is defined as AQLQ(S)+12 (End of treatment - baseline)\>=0.5. No change is defined as AQLQ(S)+12 (End of treatment - baseline) \>-0.5 and \<0.5. Deterioration is defined as AQLQ(S)+12 (End of treatment - baseline) \<= -0.5. Baseline is defined as the last AQLQ(S)+12 score prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable score at week 28 are considered as non-responder. |
| Extent of Exposure | From first dose to Week 24 | Duration of exposure from first dose date to last dose date. |
| Serum Concentration of Benralizumab | Pre-first dose to Week 36 | Pre-dose serum concentrations at each visit |
| Anti-drug Antibody Response | From baseline to follow-up Week 36 | Number and percentage of patients in different ADA response categories |
| Percent Change From Baseline in Blood Eosinophil Counts | Change from baseline at Week 28 | Percent change from baseline in blood eosinophil counts at week 28 |
| Total Lung Capacity | From baseline to Week 28 | Change from baseline in total lung capacity |
| Residual Volume | From baseline to Week 28 | Change from baseline in residual volume |
| Vital Capacity | From baseline to Week 28 | Change from baseline in vital capacity |
| Functional Residual Capacity | From baseline to Week 28 | Change from baseline in functional residual capacity |
| Inspiratory Capacity | From baseline to Week 28 | Change from baseline in inspiratory capacity |
| Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow) | Change from baseline at week 28 | Morning peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. |
Countries
Argentina, Bulgaria, Canada, Chile, France, Germany, Poland, South Korea, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Pre-assignment details
369 participants signed informed consent. 271 entered run in/OCS optimization period. 220 participants were randomized to receive treatment with benralizumab 30 mg Q4W, Q8W, or placebo. Of the 220 patients randomised, all (100.0%) received treatment with study drug
Participants by arm
| Arm | Count |
|---|---|
| Benralizumab 30 mg q.4 Weeks Benralizumab administered subcutaneously every 4 weeks | 72 |
| Benralizumab 30 mg q.8 Weeks Benralizumab administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks | 73 |
| Placebo Placebo administered subcutaneously | 75 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Study specific withdrawal criteria | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 0 |
Baseline characteristics
| Characteristic | Benralizumab 30 mg q.4 Weeks | Benralizumab 30 mg q.8 Weeks | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 50.2 Years STANDARD_DEVIATION 12 | 52.9 Years STANDARD_DEVIATION 10.1 | 49.9 Years STANDARD_DEVIATION 11.7 | 51.0 Years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 40 Participants | 47 Participants | 48 Participants | 135 Participants |
| Sex: Female, Male Male | 32 Participants | 26 Participants | 27 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 72 | 34 / 73 | 49 / 75 |
| serious Total, serious adverse events | 7 / 72 | 7 / 73 | 14 / 75 |
Outcome results
Primary
Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control
Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control | 75.00 Percent |
| Benralizumab 30 mg q.8 Weeks | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control | 75.00 Percent |
| Placebo | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control | 25.00 Percent |
p-value: <0.00195% CI: [16.7, 50]Wilcoxon (Mann-Whitney)
p-value: <0.00195% CI: [20.8, 50]Wilcoxon (Mann-Whitney)
Secondary
ACQ-6 Responders (Improvement) at Week 28
Improvement is defined as ACQ-6 (End of treatment - baseline) \<= -0.5. No change is defined as ACQ-6 (End of treatment - baseline) \>-0.5 and \<0.5. Deterioration is defined as ACQ-6 (End of treatment - baseline) \>= 0.5. ACQ-6 score is defined as the average of the first 6 items of the ACQ questionnaire on symptoms, activity limitations and rescue medication.Scores range from 0 (totally controlled) to 6 (severely uncontrolled). Baseline is defined as the last non-missing value prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable ACQ-6 at week 28 are considered non-responder.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | ACQ-6 Responders (Improvement) at Week 28 | 41 Participants | 0.95 |
| Benralizumab 30 mg q.8 Weeks | ACQ-6 Responders (Improvement) at Week 28 | 46 Participants | 1.09 |
| Placebo | ACQ-6 Responders (Improvement) at Week 28 | 41 Participants | 1.1 |
p-value: 0.65895% CI: [0.592, 2.295]Regression, Logistic
p-value: 0.15595% CI: [0.826, 3.34]Regression, Logistic
Secondary
Anti-drug Antibody Response
Number and percentage of patients in different ADA response categories
Time frame: From baseline to follow-up Week 36
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Positive at any visit | 5 Participants |
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Baseline and Post-baseline Postive | 0 Participants |
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Only post-baseline positive | 5 Participants |
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Only baseline positive | 0 Participants |
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Persistently positive | 4 Participants |
| Benralizumab 30 mg q.4 Weeks | Anti-drug Antibody Response | Transient positive | 1 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Transient positive | 0 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Positive at any visit | 7 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Only baseline positive | 1 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Persistently positive | 6 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Baseline and Post-baseline Postive | 0 Participants |
| Benralizumab 30 mg q.8 Weeks | Anti-drug Antibody Response | Only post-baseline positive | 6 Participants |
| Placebo | Anti-drug Antibody Response | Baseline and Post-baseline Postive | 3 Participants |
| Placebo | Anti-drug Antibody Response | Only post-baseline positive | 3 Participants |
| Placebo | Anti-drug Antibody Response | Transient positive | 1 Participants |
| Placebo | Anti-drug Antibody Response | Only baseline positive | 0 Participants |
| Placebo | Anti-drug Antibody Response | Positive at any visit | 6 Participants |
| Placebo | Anti-drug Antibody Response | Persistently positive | 5 Participants |
Secondary
AQLQ(s)+12 Responders (Improvement) at Week 28
AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. Improvement is defined as AQLQ(S)+12 (End of treatment - baseline)\>=0.5. No change is defined as AQLQ(S)+12 (End of treatment - baseline) \>-0.5 and \<0.5. Deterioration is defined as AQLQ(S)+12 (End of treatment - baseline) \<= -0.5. Baseline is defined as the last AQLQ(S)+12 score prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable score at week 28 are considered as non-responder.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | AQLQ(s)+12 Responders (Improvement) at Week 28 | 43 Participants | 0.95 |
| Benralizumab 30 mg q.8 Weeks | AQLQ(s)+12 Responders (Improvement) at Week 28 | 44 Participants | 1.09 |
| Placebo | AQLQ(s)+12 Responders (Improvement) at Week 28 | 39 Participants | 1.1 |
p-value: 0.2295% CI: [0.773, 3.06]Regression, Logistic
p-value: 0.10895% CI: [0.882, 3.605]Regression, Logistic
Secondary
Change From Baseline at Week 28 in AQLQ(S)+12 (Overall)
AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of \>=0.5 are considered clinically meaningful.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline at Week 28 in AQLQ(S)+12 (Overall) | 0.90 Scores on a scale | Standard Deviation 0.93 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline at Week 28 in AQLQ(S)+12 (Overall) | 1.05 Scores on a scale | Standard Deviation 1.04 |
| Placebo | Change From Baseline at Week 28 in AQLQ(S)+12 (Overall) | 0.67 Scores on a scale | Standard Deviation 1.1 |
p-value: 0.15195% CI: [-0.08, 0.53]Mixed Models Analysis
p-value: 0.00495% CI: [0.14, 0.76]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in ACQ-6
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. Mean scores of \<=0.75 indicates well-controlled asthma, scores between 0.75 to \<=1.5 indicate partly controlled asthma, and \>1.5 indicates not well controlled asthma.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in ACQ-6 | -0.86 Scores on a scale | Standard Deviation 0.95 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in ACQ-6 | -1.09 Scores on a scale | Standard Deviation 1.09 |
| Placebo | Change From Baseline to Week 28 in ACQ-6 | -0.68 Scores on a scale | Standard Deviation 1.1 |
p-value: 0.13995% CI: [-0.55, 0.08]Mixed Models Analysis
p-value: 0.00195% CI: [-0.86, -0.23]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime)
Asthma symptoms during daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime) | -0.32 Scores on a scale | Standard Deviation 0.56 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime) | -0.44 Scores on a scale | Standard Deviation 0.52 |
| Placebo | Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime) | -0.32 Scores on a scale | Standard Deviation 0.57 |
p-value: 0.99895% CI: [-0.18, 0.18]Mixed Models Analysis
p-value: 0.17795% CI: [-0.3, 0.05]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime)
Asthma symptoms during night time are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime) | -0.27 Scores on a scale | Standard Deviation 0.51 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime) | -0.34 Scores on a scale | Standard Deviation 0.54 |
| Placebo | Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime) | -0.27 Scores on a scale | Standard Deviation 0.54 |
p-value: 0.97395% CI: [-0.17, 0.17]Mixed Models Analysis
p-value: 0.4895% CI: [-0.23, 0.11]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Asthma Symptom Scores (Total)
Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Total) | -0.58 Scores on a scale | Standard Deviation 1.03 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Asthma Symptom Scores (Total) | -0.77 Scores on a scale | Standard Deviation 1.03 |
| Placebo | Change From Baseline to Week 28 in Asthma Symptom Scores (Total) | -0.58 Scores on a scale | Standard Deviation 1.03 |
p-value: 0.94795% CI: [-0.35, 0.32]Mixed Models Analysis
p-value: 0.29195% CI: [-0.51, 0.16]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow)
Evening peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow) | 21.885 Liter/min | Standard Deviation 83.136 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow) | 34.157 Liter/min | Standard Deviation 69.287 |
| Placebo | Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow) | 2.933 Liter/min | Standard Deviation 72.302 |
p-value: 0.23795% CI: [-10.08, 40.46]Mixed Models Analysis
p-value: 0.01495% CI: [6.32, 56.71]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow)
Morning peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow) | 32.697 Liter/min | Standard Deviation 89.457 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow) | 43.022 Liter/min | Standard Deviation 73.303 |
| Placebo | Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow) | 10.884 Liter/min | Standard Deviation 69.356 |
p-value: 0.14395% CI: [-6.58, 45.07]Mixed Models Analysis
p-value: 0.02395% CI: [4.26, 55.76]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Pre-bronchodilator FEV1
Baseline is defined as the last non-missing value prior to the first dose of study treatment. Change from baseline to Week 28 in two treatment groups is compared to placebo group.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Pre-bronchodilator FEV1 | 0.230 Liter | Standard Deviation 0.429 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Pre-bronchodilator FEV1 | 0.255 Liter | Standard Deviation 0.508 |
| Placebo | Change From Baseline to Week 28 in Pre-bronchodilator FEV1 | 0.114 Liter | Standard Deviation 0.401 |
p-value: 0.15395% CI: [-0.04, 0.251]Mixed Models Analysis
p-value: 0.12995% CI: [-0.033, 0.258]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in Rescue Medication Use
Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this will be considered as missing. The number of inhalations (puffs) per day will be calculated as follows: Number of night inhaler puffs + 2 x \[number of night nebulizer times\] + number of day inhaler puffs + 2 x \[number of day nebulizer times\].
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in Rescue Medication Use | -1.39 number of puffs per day | Standard Deviation 2.86 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in Rescue Medication Use | -2.58 number of puffs per day | Standard Deviation 4.36 |
| Placebo | Change From Baseline to Week 28 in Rescue Medication Use | -1.07 number of puffs per day | Standard Deviation 2.86 |
p-value: 0.39795% CI: [-1.44, 0.57]Mixed Models Analysis
p-value: 0.00695% CI: [-2.42, -0.41]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication
Baseline is defined as the proportion of nights from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly proportions based on daily diary data. If more than 50% of data are missing in a 14 day period then this will be considered as missing.Proportion of nights with noctural awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data.
Time frame: Change from baseline at week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication | -0.158 Proportion | Standard Deviation 0.283 |
| Benralizumab 30 mg q.8 Weeks | Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication | -0.2 Proportion | Standard Deviation 0.337 |
| Placebo | Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication | -0.186 Proportion | Standard Deviation 0.344 |
p-value: 0.74295% CI: [-0.08, 0.11]Mixed Models Analysis
p-value: 0.69395% CI: [-0.11, 0.07]Mixed Models Analysis
Secondary
Extent of Exposure
Duration of exposure from first dose date to last dose date.
Time frame: From first dose to Week 24
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Extent of Exposure | 162.53 Days | Standard Deviation 30.09 |
| Benralizumab 30 mg q.8 Weeks | Extent of Exposure | 159.77 Days | Standard Deviation 35.781 |
| Placebo | Extent of Exposure | 167.05 Days | Standard Deviation 10.697 |
Secondary
Functional Residual Capacity
Change from baseline in functional residual capacity
Time frame: From baseline to Week 28
Population: Global Sputum Substudy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Functional Residual Capacity | Week 12 (n=17,23, 18) | -0.05 Liter | Standard Deviation 1.06 |
| Benralizumab 30 mg q.4 Weeks | Functional Residual Capacity | Week 28 (n=13,18, 15) | -0.15 Liter | Standard Deviation 1.49 |
| Benralizumab 30 mg q.8 Weeks | Functional Residual Capacity | Week 12 (n=17,23, 18) | -0.09 Liter | Standard Deviation 0.74 |
| Benralizumab 30 mg q.8 Weeks | Functional Residual Capacity | Week 28 (n=13,18, 15) | -0.26 Liter | Standard Deviation 0.74 |
| Placebo | Functional Residual Capacity | Week 12 (n=17,23, 18) | -0.38 Liter | Standard Deviation 0.99 |
| Placebo | Functional Residual Capacity | Week 28 (n=13,18, 15) | -0.43 Liter | Standard Deviation 1.25 |
Secondary
Inspiratory Capacity
Change from baseline in inspiratory capacity
Time frame: From baseline to Week 28
Population: Global Sputum Substudy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Inspiratory Capacity | Week 12 (n=17, 23, 17) | 0.44 Liter | Standard Deviation 1.22 |
| Benralizumab 30 mg q.4 Weeks | Inspiratory Capacity | Week 28 (n=14, 17, 15) | 0.52 Liter | Standard Deviation 1.16 |
| Benralizumab 30 mg q.8 Weeks | Inspiratory Capacity | Week 12 (n=17, 23, 17) | 0.14 Liter | Standard Deviation 0.88 |
| Benralizumab 30 mg q.8 Weeks | Inspiratory Capacity | Week 28 (n=14, 17, 15) | 0.09 Liter | Standard Deviation 1.01 |
| Placebo | Inspiratory Capacity | Week 12 (n=17, 23, 17) | -0.01 Liter | Standard Deviation 0.4 |
| Placebo | Inspiratory Capacity | Week 28 (n=14, 17, 15) | -0.02 Liter | Standard Deviation 0.4 |
Secondary
Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control
Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=90% reduction | 24 Participants |
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=75% reduction | 38 Participants |
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=50% reduction | 48 Participants |
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >0% reduction | 55 Participants |
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | No change or any increase | 17 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >0% reduction | 58 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=50% reduction | 48 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | No change or any increase | 15 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=90% reduction | 27 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=75% reduction | 37 Participants |
| Placebo | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=90% reduction | 9 Participants |
| Placebo | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=75% reduction | 15 Participants |
| Placebo | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >0% reduction | 40 Participants |
| Placebo | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | No change or any increase | 35 Participants |
| Placebo | Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control | >=50% reduction | 28 Participants |
p-value: <0.00195% CI: [2.22, 7.57]proportional odds model
p-value: <0.00195% CI: [2.22, 7.63]proportional odds model
Secondary
Number and Percentage of Patients With ≥1 Asthma Exacerbation
Number and percentage of patients with at least one post randomisation asthma exacerbation.
Time frame: Immediately following the randomisation through Study Week 28
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Number and Percentage of Patients With ≥1 Asthma Exacerbation | 19 Participants |
| Benralizumab 30 mg q.8 Weeks | Number and Percentage of Patients With ≥1 Asthma Exacerbation | 17 Participants |
| Placebo | Number and Percentage of Patients With ≥1 Asthma Exacerbation | 39 Participants |
p-value: 0.00195% CI: [0.16, 0.65]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [0.14, 0.56]Cochran-Mantel-Haenszel
Secondary
Number of Days in Hospital Due to Asthma
Number of days in hospital due to asthma, if none, 0 day is considered
Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Number of Days in Hospital Due to Asthma | 0.3 Days | Standard Deviation 1.41 |
| Benralizumab 30 mg q.8 Weeks | Number of Days in Hospital Due to Asthma | 0.5 Days | Standard Deviation 3.86 |
| Placebo | Number of Days in Hospital Due to Asthma | 1.2 Days | Standard Deviation 6.66 |
Secondary
Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL
Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set, baseline blood eosinophil \>=300/uL
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL | 75.00 Percent |
| Benralizumab 30 mg q.8 Weeks | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL | 75.00 Percent |
| Placebo | Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL | 0.00 Percent |
p-value: <0.00195% CI: [25, 66.7]Wilcoxon (Mann-Whitney)
p-value: <0.00195% CI: [25, 66.7]Wilcoxon (Mann-Whitney)
Secondary
Percent Change From Baseline in Blood Eosinophil Counts
Percent change from baseline in blood eosinophil counts at week 28
Time frame: Change from baseline at Week 28
Population: Full analysis set. Number of participants analyzed contains number of participants who had value at Week 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Percent Change From Baseline in Blood Eosinophil Counts | -97.4 percent change | Standard Deviation 12.93 |
| Benralizumab 30 mg q.8 Weeks | Percent Change From Baseline in Blood Eosinophil Counts | -94.9 percent change | Standard Deviation 16.54 |
| Placebo | Percent Change From Baseline in Blood Eosinophil Counts | 45.5 percent change | Standard Deviation 239.51 |
p-value: <0.00195% CI: [-220.1, -104.3]Mixed Models Analysis
p-value: <0.00195% CI: [-217.9, -100.9]Mixed Models Analysis
Secondary
Residual Volume
Change from baseline in residual volume
Time frame: From baseline to Week 28
Population: Global Sputum Substudy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Residual Volume | Week 12 (n=17, 23, 17) | 0.02 Liter | Standard Deviation 1 |
| Benralizumab 30 mg q.4 Weeks | Residual Volume | Week 28 (n=14, 18, 15) | 0.07 Liter | Standard Deviation 1.34 |
| Benralizumab 30 mg q.8 Weeks | Residual Volume | Week 12 (n=17, 23, 17) | -0.22 Liter | Standard Deviation 0.74 |
| Benralizumab 30 mg q.8 Weeks | Residual Volume | Week 28 (n=14, 18, 15) | -0.31 Liter | Standard Deviation 0.71 |
| Placebo | Residual Volume | Week 12 (n=17, 23, 17) | -0.35 Liter | Standard Deviation 1.03 |
| Placebo | Residual Volume | Week 28 (n=14, 18, 15) | -0.41 Liter | Standard Deviation 1.27 |
Secondary
Serum Concentration of Benralizumab
Pre-dose serum concentrations at each visit
Time frame: Pre-first dose to Week 36
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 36 (n=2, 4) | 11.11 ng/mL | Geometric Coefficient of Variation 2140.87 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 12 (n=68, 67) | 1319.14 ng/mL | Geometric Coefficient of Variation 66.05 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 4 (n=67, 71) | 804.37 ng/mL | Geometric Coefficient of Variation 52.77 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 16 (n=67,67) | 1337.98 ng/mL | Geometric Coefficient of Variation 118.9 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Baseline (n=69, 71) | NA ng/mL | — |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 24 (n=65, 66) | 1162.62 ng/mL | Geometric Coefficient of Variation 151.35 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | week 8 (n=66, 69) | 1152.96 ng/mL | Geometric Coefficient of Variation 53.16 |
| Benralizumab 30 mg q.4 Weeks | Serum Concentration of Benralizumab | Week 28 (n=65, 65) | 1125.96 ng/mL | Geometric Coefficient of Variation 173.79 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | week 8 (n=66, 69) | 1019.65 ng/mL | Geometric Coefficient of Variation 89.51 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 36 (n=2, 4) | 5.92 ng/mL | Geometric Coefficient of Variation 1230.68 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Baseline (n=69, 71) | NA ng/mL | — |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 4 (n=67, 71) | 721.42 ng/mL | Geometric Coefficient of Variation 52.3 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 28 (n=65, 65) | 684.57 ng/mL | Geometric Coefficient of Variation 205.67 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 12 (n=68, 67) | 1057.91 ng/mL | Geometric Coefficient of Variation 125.74 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 16 (n=67,67) | 303.54 ng/mL | Geometric Coefficient of Variation 144.53 |
| Benralizumab 30 mg q.8 Weeks | Serum Concentration of Benralizumab | Week 24 (n=65, 66) | 185.17 ng/mL | Geometric Coefficient of Variation 278.32 |
Secondary
The Annualized Rate of Asthma Exacerbation
The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up.
Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Annualized Rate of Asthma Exacerbation | 0.83 events/year |
| Benralizumab 30 mg q.8 Weeks | The Annualized Rate of Asthma Exacerbation | 0.54 events/year |
| Placebo | The Annualized Rate of Asthma Exacerbation | 1.83 events/year |
p-value: 0.00395% CI: [0.27, 0.76]negative binomial model
p-value: <0.00195% CI: [0.17, 0.53]negative binomial model
Secondary
The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization
The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator that are associated with an emergency room visit or a hospitalization adjusted by the time of follow-up.
Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization | 0.14 events/year |
| Benralizumab 30 mg q.8 Weeks | The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization | 0.02 events/year |
| Placebo | The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization | 0.32 events/year |
p-value: 0.18795% CI: [0.13, 1.49]negative binomial model
p-value: 0.01895% CI: [0.01, 0.63]negative binomial model
Secondary
The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control
Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 48 Participants |
| Benralizumab 30 mg q.8 Weeks | The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 48 Participants |
| Placebo | The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 28 Participants |
p-value: <0.00195% CI: [1.79, 7.22]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [1.57, 5.86]Cochran-Mantel-Haenszel
Secondary
The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control
Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set, eligible for 100% reduction (ie, patients with baseline OCS dose \<= 12.5 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 22 Participants |
| Benralizumab 30 mg q.8 Weeks | The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 22 Participants |
| Placebo | The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control | 8 Participants |
p-value: <0.00195% CI: [1.92, 14.21]Cochran-Mantel-Haenszel
p-value: 0.00295% CI: [1.58, 11.12]Cochran-Mantel-Haenszel
Secondary
The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control.
Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control. | 22 Participants |
| Benralizumab 30 mg q.8 Weeks | The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control. | 25 Participants |
| Placebo | The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control. | 38 Participants |
p-value: 0.01295% CI: [0.21, 0.83]Cochran-Mantel-Haenszel
p-value: 0.05395% CI: [0.27, 1.01]Cochran-Mantel-Haenszel
Secondary
The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control
Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
Time frame: Week 28
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control | 44 Participants |
| Benralizumab 30 mg q.8 Weeks | The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control | 43 Participants |
| Placebo | The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control | 25 Participants |
p-value: <0.00195% CI: [1.6, 6.23]Cochran-Mantel-Haenszel
p-value: 0.00295% CI: [1.41, 5.31]Cochran-Mantel-Haenszel
Secondary
Time to the First Asthma Exacerbation
Time to the first occurrence of asthma exacerbation post randomisation
Time frame: The time from randomisation to the date of first asthma exacerbation over 28 weeks
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Time to the First Asthma Exacerbation | NA Days |
| Benralizumab 30 mg q.8 Weeks | Time to the First Asthma Exacerbation | NA Days |
| Placebo | Time to the First Asthma Exacerbation | 155 Days |
p-value: <0.00195% CI: [0.22, 0.66]Regression, Cox
p-value: <0.00195% CI: [0.17, 0.57]Regression, Cox
Secondary
Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit
Time to the first exacerbation requiring hospitalization or ER visit post randomisation
Time frame: The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit | NA Days |
| Benralizumab 30 mg q.8 Weeks | Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit | NA Days |
| Placebo | Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit | NA Days |
p-value: 0.29195% CI: [0.14, 1.64]Regression, Cox
p-value: 0.04295% CI: [0.01, 0.63]Regression, Cox
Secondary
Total Lung Capacity
Change from baseline in total lung capacity
Time frame: From baseline to Week 28
Population: Global Sputum Substudy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Total Lung Capacity | Week 12 (n=17, 23, 17) | -0.02 Liter | Standard Deviation 0.95 |
| Benralizumab 30 mg q.4 Weeks | Total Lung Capacity | Week 28 (n=14, 18, 15) | 0.11 Liter | Standard Deviation 1.31 |
| Benralizumab 30 mg q.8 Weeks | Total Lung Capacity | Week 12 (n=17, 23, 17) | -0.07 Liter | Standard Deviation 0.68 |
| Benralizumab 30 mg q.8 Weeks | Total Lung Capacity | Week 28 (n=14, 18, 15) | -0.21 Liter | Standard Deviation 0.7 |
| Placebo | Total Lung Capacity | Week 12 (n=17, 23, 17) | -0.30 Liter | Standard Deviation 1.08 |
| Placebo | Total Lung Capacity | Week 28 (n=14, 18, 15) | -0.47 Liter | Standard Deviation 1.47 |
Secondary
Vital Capacity
Change from baseline in vital capacity
Time frame: From baseline to Week 28
Population: Global Sputum Substudy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg q.4 Weeks | Vital Capacity | Week 12 (n=17, 24, 18) | 0.15 Liter | Standard Deviation 0.8 |
| Benralizumab 30 mg q.4 Weeks | Vital Capacity | Week 28 (n=14, 18, 15) | 0.15 Liter | Standard Deviation 0.41 |
| Benralizumab 30 mg q.8 Weeks | Vital Capacity | Week 28 (n=14, 18, 15) | 0.11 Liter | Standard Deviation 0.48 |
| Benralizumab 30 mg q.8 Weeks | Vital Capacity | Week 12 (n=17, 24, 18) | 0.18 Liter | Standard Deviation 0.35 |
| Placebo | Vital Capacity | Week 28 (n=14, 18, 15) | -0.08 Liter | Standard Deviation 0.41 |
| Placebo | Vital Capacity | Week 12 (n=17, 24, 18) | 0.13 Liter | Standard Deviation 0.89 |