Asthma
Conditions
Keywords
Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases,
Brief summary
The purpose of this trial is to confirm the safety and clinical benefit of benralizumab administration in asthma patients with mild to moderate persistent asthma in order to gain an understanding of the benefit/risk of benralizumab across the spectrum of asthma disease.
Interventions
BIOLOGICALBenralizumab
Benralizumab administered subcutaneously every 4 weeks
BIOLOGICALPlacebo
Placebo administered subcutaneously every 4 weeks
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines. * Female and male aged 18 to 75 years, inclusively, at the time of Visit 1. * Weight of ≥40 kg. * Evidence of asthma as documented by post-bronchodilator (post-BD) reversibility in FEV1 of ≥ 12% demonstrated at Visit 2. * Documented use of 1 of the following types of asthma therapy at time of informed consent: Low- to medium-dose ICS (ie, 100 to 500 μg fluticasone dry powder formulation equivalents total daily dose) with or without other controller medications, eg, an LTRA and/or theophylline or Low-dose ICS/LABA fixed combination therapy (eg, the lowest regular maintenance dose approved in the local country will meet this criterion) * Morning pre-bronchodilator (pre-BD) FEV1 of \> 50% to ≤ 90% predicted at Visit 2.
Exclusion criteria
* Clinically important pulmonary disease other than asthma (eg, active lung infection, 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 (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome). * 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 * nfluence the findings of the studies or their interpretations,- Impede the patient's ability to complete the entire duration of study. * Known history of allergy or reaction to the investigational product formulation. * History of anaphylaxis to any biologic therapy.- History of Guillain-Barré syndrome. * A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.- 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. * Any clinically significant abnormal findings in physical examination, vital signs, hematology, 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. * Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll. * A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. * History of cancer: * Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained. * Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Baseline, Week 4, Week 8 and Week 12 | The FEV1 (L) change from baseline are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) analysis with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline pre-bronchodilator FEV1 (L) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | The changes from baseline of weekly average of evening PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline evening PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Change From Baseline in Total Asthma Symptom Score at Week 12 | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | Asthma symptoms were recorded by the patient each morning and evening in the asthma daily diary. Symptoms were recorded using a scale of 0-3, where 0 indicates no asthma symptoms. The daily asthma symptom total score was calculated by taking the sum of the daytime score recorded in the evening and the nighttime score recorded the following morning. The weekly total asthma score was averaged from the daily scores over a 7 day period, with score ranging from 0 to 6, where 0 indicates no asthma symptoms. The changes from baseline of weekly total asthma score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline total asthma score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | The number of rescue medication inhalations and nebulizer treatments taken were recorded by the patient in the asthma daily diary twice daily. The number of inhalations (puffs) per day was calculated as \[number of night inhaler puffs\] + 2 x \[number of night nebulizer times\] + number of day inhaler puffs + 2 x \[number of day nebulizer times\]. The changes from baseline in weekly total asthma rescue medication use (puffs) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline total asthma rescue medication use (puffs) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | Nocturnal awakenings due to asthma symptoms and requiring rescue medication use was recorded by the patient in the asthma daily diary each morning. Proportion of nights with nocturnal awakenings was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data for awakening due to asthma. The outcome variable for proportion of nights with nocturnal awakenings was the change from baseline at Week 12 in weekly proportion of nights with nocturnal awakenings. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline proportion of nights with nocturnal awakenings as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12 | The changes from baseline of weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline morning PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Asthma Exacerbations | Up to Week 12 | An asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for at least 3 days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids) or an emergency room or urgent care visit (defined as evaluation and treatment for \<24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above) or an inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. Number of patients experiencing an event included in the definition of asthma exacerbation was presented. |
| Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Baseline and Week 12 | The asthma quality of life questionnaire for 12 years and older, AQLQ(S)+12, consists of 32 questions; all assessed on a 7-point scale from 7 to 1, where 7 represents no impairment and 1 represents severe impairment. The 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains. The overall score is calculated as the mean response to all questions. The changes from baseline of AQLQ(S)+12 score are compared between benralizumab 30 mg Q4W and placebo by using the analyse of covariance (ANCOVA) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL) and region (Europe or North America) as fixed effects and baseline AQLQ(S)+12 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
| Serum Concentrations (ng/mL) | Baseline, Week 12 and Week 20 | Blood samples (processed to serum) for pharmacokinetic assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Serum concentrations of benralizumab were determined using a validated electrochemiluminescent (ECL) immunoassay. |
| Peripheral Blood Eosinophil Levels | Baseline, Week 12 and Week 20 | Peripheral blood eosinophil levels assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Changes at Week 12 (respectively at Week 20) were calculated based on patients with both baseline and Week 12 (respectively Week 20). |
| Change From Baseline in Mean ACQ-6 Score at Week 12 | Baseline, Week 4, Week 8 and Week 12 | The asthma control questionnaire, ACQ-6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. The changes from baseline of ACQ-6 score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline ACQ-6 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12. |
Countries
Canada, Germany, Hungary, Poland, Slovakia, United States
Participant flow
Recruitment details
After enrollment, eligible patients entered a 2- to 4-week screening/run-in period and were converted to budesonide dry powder inhaler twice daily for the duration of the study. Patients who continued to meet eligibility criteria at the end of the run-in period entered a 12 weeks double-blind treatment period followed by two follow-up visits.
Pre-assignment details
Eligible adult patients were stratified by baseline blood eosinophil count (\<300 cells/μL or ≥300 cells/μL) and by region (USA versus Rest of the World per the IVRS). Patients were then randomized to either benralizumab 30 mg Q4W or placebo in a 1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Benralizumab 30 mg Q4W Benralizumab administered subcutaneously every 4 weeks | 106 |
| Placebo Placebo administered subcutaneously every 4 weeks | 105 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not willing to perform all FU visits | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Benralizumab 30 mg Q4W | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 48.3 Years STANDARD_DEVIATION 14.4 | 51.1 Years STANDARD_DEVIATION 12.6 | 49.7 Years STANDARD_DEVIATION 13.58 |
| Age, Customized >=18-<50 years | 49 Participants | 44 Participants | 93 Participants |
| Age, Customized >=50-<65 years | 43 Participants | 46 Participants | 89 Participants |
| Age, Customized >=65-<=75 years | 14 Participants | 15 Participants | 29 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 100 Participants | 102 Participants | 202 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 98 Participants | 99 Participants | 197 Participants |
| Sex: Female, Male Female | 62 Participants | 67 Participants | 129 Participants |
| Sex: Female, Male Male | 44 Participants | 38 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 106 | 14 / 105 |
| serious Total, serious adverse events | 2 / 106 | 2 / 105 |
Outcome results
Primary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12
The FEV1 (L) change from baseline are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) analysis with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline pre-bronchodilator FEV1 (L) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 4, Week 8 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Baseline | 2.248 Litre | Standard Deviation 0.6062 |
| Benralizumab 30 mg Q4W | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Week 12 | 2.310 Litre | Standard Deviation 0.6702 |
| Benralizumab 30 mg Q4W | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Change from baseline at Week 12 | 0.057 Litre | Standard Deviation 0.2734 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Baseline | 2.246 Litre | Standard Deviation 0.7677 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Week 12 | 2.261 Litre | Standard Deviation 0.7959 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12 | Change from baseline at Week 12 | -0.016 Litre | Standard Deviation 0.235 |
Comparison: The null hypothesis was: H0: Change from baseline in pre-bronchodilator FEV1 (L) at Week 12 (benralizumab vs placebo)=0.p-value: 0.0495% CI: [0, 0.15]Mixed Models Analysis
Secondary
Asthma Exacerbations
An asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for at least 3 days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids) or an emergency room or urgent care visit (defined as evaluation and treatment for \<24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above) or an inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. Number of patients experiencing an event included in the definition of asthma exacerbation was presented.
Time frame: Up to Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Benralizumab 30 mg Q4W | Asthma Exacerbations | 0 exacerbation | 105 Patients per number of exacerbations |
| Benralizumab 30 mg Q4W | Asthma Exacerbations | 1 exacerbation | 0 Patients per number of exacerbations |
| Benralizumab 30 mg Q4W | Asthma Exacerbations | 2 exacerbations | 1 Patients per number of exacerbations |
| Placebo | Asthma Exacerbations | 0 exacerbation | 103 Patients per number of exacerbations |
| Placebo | Asthma Exacerbations | 1 exacerbation | 2 Patients per number of exacerbations |
| Placebo | Asthma Exacerbations | 2 exacerbations | 0 Patients per number of exacerbations |
Secondary
Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12
The asthma quality of life questionnaire for 12 years and older, AQLQ(S)+12, consists of 32 questions; all assessed on a 7-point scale from 7 to 1, where 7 represents no impairment and 1 represents severe impairment. The 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains. The overall score is calculated as the mean response to all questions. The changes from baseline of AQLQ(S)+12 score are compared between benralizumab 30 mg Q4W and placebo by using the analyse of covariance (ANCOVA) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL) and region (Europe or North America) as fixed effects and baseline AQLQ(S)+12 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - W12 | 5.503 Scores on a scale | Standard Deviation 0.9672 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - Baseline | 4.649 Scores on a scale | Standard Deviation 1.0367 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - Baseline | 4.825 Scores on a scale | Standard Deviation 0.9787 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - Baseline | 4.95 Scores on a scale | Standard Deviation 1.277 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - W12 | 5.380 Scores on a scale | Standard Deviation 1.0076 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - W12 | 5.54 Scores on a scale | Standard Deviation 1.215 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - CFB at W12 | 0.585 Scores on a scale | Standard Deviation 0.8675 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - CFB at W12 | 0.57 Scores on a scale | Standard Deviation 1.094 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - CFB at W12 | 0.727 Scores on a scale | Standard Deviation 0.989 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - Baseline | 4.658 Scores on a scale | Standard Deviation 1.332 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - W12 | 5.415 Scores on a scale | Standard Deviation 0.9478 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - W12 | 5.120 Scores on a scale | Standard Deviation 1.291 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - Baseline | 5.017 Scores on a scale | Standard Deviation 1.0029 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - CFB at W12 | 0.466 Scores on a scale | Standard Deviation 1.0135 |
| Benralizumab 30 mg Q4W | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - CFB at W12 | 0.481 Scores on a scale | Standard Deviation 0.8156 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - CFB at W12 | 0.216 Scores on a scale | Standard Deviation 0.9505 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - Baseline | 4.895 Scores on a scale | Standard Deviation 1.0339 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - CFB at W12 | 0.357 Scores on a scale | Standard Deviation 0.7979 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - Baseline | 4.692 Scores on a scale | Standard Deviation 1.083 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - W12 | 5.212 Scores on a scale | Standard Deviation 1.1373 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Symptoms score - CFB at W12 | 0.483 Scores on a scale | Standard Deviation 0.9243 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - Baseline | 5.048 Scores on a scale | Standard Deviation 1.0277 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - W12 | 5.343 Scores on a scale | Standard Deviation 1.0803 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Activity limitations score - CFB at W12 | 0.275 Scores on a scale | Standard Deviation 0.8105 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - Baseline | 5.04 Scores on a scale | Standard Deviation 1.373 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - W12 | 5.45 Scores on a scale | Standard Deviation 1.307 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Emotional function score - CFB at W12 | 0.35 Scores on a scale | Standard Deviation 1.014 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - Baseline | 4.905 Scores on a scale | Standard Deviation 1.3554 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Environmental stimuli score - W12 | 5.130 Scores on a scale | Standard Deviation 1.3372 |
| Placebo | Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12 | Total score - W12 | 5.284 Scores on a scale | Standard Deviation 1.0851 |
Comparison: Parameter: Total scorep-value: 0.05595% CI: [0, 0.42]ANCOVA
Comparison: Parameter: Symptoms scorep-value: 0.06395% CI: [-0.01, 0.47]ANCOVA
Comparison: Parameter: Activity limitation scorep-value: 0.06195% CI: [-0.01, 0.41]ANCOVA
Comparison: Parameter: Emotional function scorep-value: 0.15695% CI: [-0.07, 0.45]ANCOVA
Comparison: Parameter: Environmental stimuli scorep-value: 0.13595% CI: [-0.06, 0.44]ANCOVA
Secondary
Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12
The changes from baseline of weekly average of evening PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline evening PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline | 326.948 L/min | Standard Deviation 97.4034 |
| Benralizumab 30 mg Q4W | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Week 12 | 330.719 L/min | Standard Deviation 106.7579 |
| Benralizumab 30 mg Q4W | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Change from baseline at Week 12 | 1.361 L/min | Standard Deviation 51.9979 |
| Placebo | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline | 316.743 L/min | Standard Deviation 116.6919 |
| Placebo | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Week 12 | 316.047 L/min | Standard Deviation 118.7 |
| Placebo | Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Change from baseline at Week 12 | -2.956 L/min | Standard Deviation 47.9136 |
p-value: 0.45695% CI: [-8.67, 19.25]Mixed Models Analysis
Secondary
Change From Baseline in Mean ACQ-6 Score at Week 12
The asthma control questionnaire, ACQ-6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. The changes from baseline of ACQ-6 score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline ACQ-6 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 4, Week 8 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Mean ACQ-6 Score at Week 12 | Baseline | 2.119 Scores on a scale | Standard Deviation 0.8423 |
| Benralizumab 30 mg Q4W | Change From Baseline in Mean ACQ-6 Score at Week 12 | Week 12 | 1.428 Scores on a scale | Standard Deviation 0.8621 |
| Benralizumab 30 mg Q4W | Change From Baseline in Mean ACQ-6 Score at Week 12 | Change from baseline at Week 12 | -0.714 Scores on a scale | Standard Deviation 0.87 |
| Placebo | Change From Baseline in Mean ACQ-6 Score at Week 12 | Baseline | 2.092 Scores on a scale | Standard Deviation 0.8975 |
| Placebo | Change From Baseline in Mean ACQ-6 Score at Week 12 | Week 12 | 1.568 Scores on a scale | Standard Deviation 1.009 |
| Placebo | Change From Baseline in Mean ACQ-6 Score at Week 12 | Change from baseline at Week 12 | -0.495 Scores on a scale | Standard Deviation 0.7908 |
p-value: 0.11495% CI: [-0.39, 0.04]Mixed Models Analysis
Secondary
Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12
The changes from baseline of weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline morning PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline | 307.413 L/min | Standard Deviation 95.9467 |
| Benralizumab 30 mg Q4W | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Week 12 | 311.041 L/min | Standard Deviation 101.8169 |
| Benralizumab 30 mg Q4W | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Change from baseline at Week 12 | 1.675 L/min | Standard Deviation 56.5182 |
| Placebo | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Change from baseline at Week 12 | -6.196 L/min | Standard Deviation 45.3077 |
| Placebo | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Baseline | 308.226 L/min | Standard Deviation 113.5895 |
| Placebo | Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12 | Week 12 | 304.037 L/min | Standard Deviation 113.2538 |
p-value: 0.23395% CI: [-5.74, 23.42]Mixed Models Analysis
Secondary
Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12
Nocturnal awakenings due to asthma symptoms and requiring rescue medication use was recorded by the patient in the asthma daily diary each morning. Proportion of nights with nocturnal awakenings was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data for awakening due to asthma. The outcome variable for proportion of nights with nocturnal awakenings was the change from baseline at Week 12 in weekly proportion of nights with nocturnal awakenings. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline proportion of nights with nocturnal awakenings as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Baseline | 0.246 Proportion of nights | Standard Deviation 0.2924 |
| Benralizumab 30 mg Q4W | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Week 12 | 0.086 Proportion of nights | Standard Deviation 0.2003 |
| Benralizumab 30 mg Q4W | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Change from baseline at Week 12 | -0.158 Proportion of nights | Standard Deviation 0.2515 |
| Placebo | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Baseline | 0.279 Proportion of nights | Standard Deviation 0.3326 |
| Placebo | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Week 12 | 0.144 Proportion of nights | Standard Deviation 0.2796 |
| Placebo | Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12 | Change from baseline at Week 12 | -0.139 Proportion of nights | Standard Deviation 0.2659 |
p-value: 0.3895% CI: [-0.08, 0.03]Mixed Models Analysis
Secondary
Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12
The number of rescue medication inhalations and nebulizer treatments taken were recorded by the patient in the asthma daily diary twice daily. The number of inhalations (puffs) per day was calculated as \[number of night inhaler puffs\] + 2 x \[number of night nebulizer times\] + number of day inhaler puffs + 2 x \[number of day nebulizer times\]. The changes from baseline in weekly total asthma rescue medication use (puffs) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline total asthma rescue medication use (puffs) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Baseline | 2.953 Puffs per day | Standard Deviation 3.0794 |
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Week 12 | 1.647 Puffs per day | Standard Deviation 2.4782 |
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Change from baseline at Week 12 | -1.098 Puffs per day | Standard Deviation 2.3588 |
| Placebo | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Change from baseline at Week 12 | -0.665 Puffs per day | Standard Deviation 2.2744 |
| Placebo | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Baseline | 2.641 Puffs per day | Standard Deviation 3.0671 |
| Placebo | Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12 | Week 12 | 2.070 Puffs per day | Standard Deviation 2.6848 |
p-value: 0.295% CI: [-0.91, 0.19]Mixed Models Analysis
Secondary
Change From Baseline in Total Asthma Symptom Score at Week 12
Asthma symptoms were recorded by the patient each morning and evening in the asthma daily diary. Symptoms were recorded using a scale of 0-3, where 0 indicates no asthma symptoms. The daily asthma symptom total score was calculated by taking the sum of the daytime score recorded in the evening and the nighttime score recorded the following morning. The weekly total asthma score was averaged from the daily scores over a 7 day period, with score ranging from 0 to 6, where 0 indicates no asthma symptoms. The changes from baseline of weekly total asthma score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit, region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline total asthma score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Population: The Full Analysis Set comprised all patients randomised and receiving any investigational product (IP), irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Symptom Score at Week 12 | Baseline | 1.934 Scores on a scale | Standard Deviation 0.931 |
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Symptom Score at Week 12 | Week 12 | 1.326 Scores on a scale | Standard Deviation 1.0448 |
| Benralizumab 30 mg Q4W | Change From Baseline in Total Asthma Symptom Score at Week 12 | Change from baseline at Week 12 | -0.567 Scores on a scale | Standard Deviation 0.7875 |
| Placebo | Change From Baseline in Total Asthma Symptom Score at Week 12 | Baseline | 1.952 Scores on a scale | Standard Deviation 1.0375 |
| Placebo | Change From Baseline in Total Asthma Symptom Score at Week 12 | Week 12 | 1.541 Scores on a scale | Standard Deviation 1.1208 |
| Placebo | Change From Baseline in Total Asthma Symptom Score at Week 12 | Change from baseline at Week 12 | -0.420 Scores on a scale | Standard Deviation 0.8767 |
p-value: 0.26695% CI: [-0.35, 0.1]Mixed Models Analysis
Secondary
Peripheral Blood Eosinophil Levels
Peripheral blood eosinophil levels assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Changes at Week 12 (respectively at Week 20) were calculated based on patients with both baseline and Week 12 (respectively Week 20).
Time frame: Baseline, Week 12 and Week 20
Population: The safety analysis set comprised all patients who received at least one dose of IP. Patients were classified according to the treatment they actually received. A patient who has on one or several occasions received active treatment was classified as active.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Benralizumab 30 mg Q4W | Peripheral Blood Eosinophil Levels | Week 12 | 0.00 Cells/µL |
| Benralizumab 30 mg Q4W | Peripheral Blood Eosinophil Levels | Week 20 | 0 Cells/µL |
| Benralizumab 30 mg Q4W | Peripheral Blood Eosinophil Levels | Change from baseline at Week 12 | -170 Cells/µL |
| Benralizumab 30 mg Q4W | Peripheral Blood Eosinophil Levels | Change from Baseline at Week 20 | -160 Cells/µL |
| Benralizumab 30 mg Q4W | Peripheral Blood Eosinophil Levels | Baseline | 170 Cells/µL |
| Placebo | Peripheral Blood Eosinophil Levels | Change from Baseline at Week 20 | 10 Cells/µL |
| Placebo | Peripheral Blood Eosinophil Levels | Baseline | 220 Cells/µL |
| Placebo | Peripheral Blood Eosinophil Levels | Week 12 | 230 Cells/µL |
| Placebo | Peripheral Blood Eosinophil Levels | Change from baseline at Week 12 | 10 Cells/µL |
| Placebo | Peripheral Blood Eosinophil Levels | Week 20 | 210 Cells/µL |
Secondary
Serum Concentrations (ng/mL)
Blood samples (processed to serum) for pharmacokinetic assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Serum concentrations of benralizumab were determined using a validated electrochemiluminescent (ECL) immunoassay.
Time frame: Baseline, Week 12 and Week 20
Population: The pharmacokinetic (PK) analysis set comprised all patients who received benralizumab and from whom PK blood samples were obtained are assumed not to be affected by factors such as protocol violations. Those patients who had at least 1 quantifiable serum PK observation post first dose were included in the PK analysis dataset.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg Q4W | Serum Concentrations (ng/mL) | Pre- 1st dose | NA ng/mL | — |
| Benralizumab 30 mg Q4W | Serum Concentrations (ng/mL) | Week 12 | 999.16 ng/mL | Geometric Coefficient of Variation 95.53 |
| Benralizumab 30 mg Q4W | Serum Concentrations (ng/mL) | Week 20 | 59.04 ng/mL | Geometric Coefficient of Variation 317.71 |