Asthma
Conditions
Keywords
Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
Brief summary
The purpose of this study is to investigate the onset and maintenance of effect of benralizumab on lung function, blood eosinophils, asthma control metrics and quality of life during 12-week treatment in patients with uncontrolled, severe asthma with eosinophilic inflammation. A subset of patients will take part in body plethysmography substudy to further investigate the effect on lung function.
Interventions
DRUGBenralizumab
Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
OTHERPlacebo
Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Female and male aged 18 to 75 years inclusively at the time of Visit 1 3. Documented current treatment with ICS and LABA for at least 30 days prior to Visit 1. The ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or equivalent daily. Additional asthma controller medications, eg, oral corticosteroids, long-acting antimuscarinics (LAMAs), LTRAs, theophylline etc. are allowed if they have been used for at least 30 days prior to Visit 1 4. History of at least 2 asthma exacerbations that required treatment with systemic corticosteroids (intramuscular (IM), intravenous (IV), or oral) in the 12 months prior to Visit 1. For patients receiving corticosteroids as a maintenance therapy, the corticosteroid treatment for the exacerbation is defined as a temporary increase of their maintenance dose. 5. Pre-bronchodilator (pre-BD) FEV1 of \< 80% predicted at Visit 2 or Visit 3 6. ACQ-6 score ≥1.5 at Visit 1 7. Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 ml) demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2 only 8. Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1 9. Women of childbearing potential (WOCBP) must use an effective form of birth control confirmed by the Investigator. WOCBP must also have negative serum pregnancy test result on Visit 1. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months prior to the planned date of randomization without an alternative medical cause. The following agespecific requirements apply: * Women \<50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. * Women ≥50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment. 10. All male patients who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of IP until 16 weeks after their last dose 11. Weight of ≥40 kg Additional inclusion criteria applicable for the Body Plethysmography substudy 1.Residual volume ≥125% of predicted at Visit 3. Inclusion criteria at randomization visit 1. At least 1 of the following within 7 days prior to randomization: * Daytime or nighttime asthma symptoms for 2 or more days; * Rescue SABA use for 2 or more days; * Nighttime awakenings due to asthma at least 1 night during the 7-day period 2. ACQ \>0.75 at Visit 4 prior to randomization. 3. A negative urine pregnancy test in WOCBP prior to administration of IP
Exclusion criteria
1. 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) 2. Life-threatening asthma defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1. 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. An upper respiratory tract infection or an asthma exacerbation that required treatment with systemic corticosteroids or an increase in regular maintenance dose of OCS during the screening/run-in period prior to randomization Visit 4 5. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could: * Affect the safety of the patient throughout the study * Influence the findings of the studies or their interpretations * Impede the patient's ability to complete the entire duration of study 6. Known history of allergy or reaction to any component of the investigational product formulation 7. History of anaphylaxis to any biologic therapy 8. History of Guillain-Barré syndrome 9. 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 10. 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 11. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening/run-in period, which in the opinion of the Investigator may put the patient at risk or interfere with study assessments 12. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained 13. 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 14. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test 15. Current smokers or former smokers with a smoking history of ≥10 pack years. A former smoker is defined as a patient who quit smoking at least 6 months prior to Visit 1 16. Current malignancy, or history of malignancy, except for: * Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained. * Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained. 17. Use of immunosuppressive medication (including but not limited to: oral corticosteroids \[for reasons other than asthma\], methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent 18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times the upper limit of normal (ULN) confirmed during screening period 19. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained 20. Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer 21. Receipt of live attenuated vaccines 30 days prior to the date of randomization 22. Receipt of any investigational medication within 30 days or 5 half-lives prior to randomization, whichever is longer 23. Previously received benralizumab (MEDI-563) 24. Planned surgical procedures during the conduct of the study 25. Currently breastfeeding or lactating women 26. Previous randomization in the present study 27. Concurrent enrolment in another interventional or post-authorization safety study (PASS). 28. AstraZeneca staff involved in the planning and/or conduct of the study 29. Employees of the study center or any other individuals involved with the conduct of the study or immediate family members of such individuals
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | From first IP dose to Day 84 | The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect. |
| Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV) | From first IP dose to Day 84 | Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Pre-BD FEV1 Responder | From first IP dose to Day 84 | Pre-BD FEV1 responder is defined as change from baseline in FEV1 \>=100 ml |
| Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | From first IP dose to Day 84 | The SGRQ is designed to measure health impairment in patients with asthma and COPD. It contains two parts: Part 1 (Questions 1 to 8) covers the patients' recollection of their symptoms over a preceding 4 weeks; Part 2, 42 items, relates to the daily activity and psychosocial impacts of the individual's respiratory condition. Total score is presented as a percentage of overall impairment, in which 100 represents the worst possible health status, while 0 indicates the best. |
| Change From Baseline to End of Treatment in FeNO | From first IP dose to Day 84 | Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement. |
| Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Duration of IP Administration | From first IP to last IP | Duration of IP administration is last IP dose date - first IP dose +1. |
| Percent Change From Baseline to End of Treatment in Eosinophils Counts | From first IP dose to Day 84 | Percent change from baseline to Day 84 |
| Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | From first IP dose to Day 84 | Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, Day 84. \[Note: Day 28, 56, 84 are presented in the Primary measure.\] |
| Change From Baseline to Post Baseline for Pre-BD FVC | From first IP dose to Day 84 | Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84. |
| Change From Baseline in ACQ-6 | From first IP dose to Day 84 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Treatment in PGI-S | From first IP dose to Day 84 | The patient global impression of severity (PGI-S) is a single item designed to capture the patient's perception of overall symptom severity at the time of the completion using a 6-point categorical response scale (no symptom \[0\] to very severe symptom \[5\]) |
| Change From Baseline to End of Treatment in CGI-C | From first IP dose to Day 84 | Clinician global impression of change (CGI-C) is used for an overall evaluation of response to treatment. The investigator is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse. |
| Change From Baseline to End of Treatment in PGI-C | From first IP dose to Day 84 | Patient global impression of change (PGI-C) is used for an overall evaluation of response to treatment. The patient is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse. |
| Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients | From first IP dose to Day 84 | Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements. |
| Serum Concentration of Benralizumab | From first dose to end of treatment period (Day 84) | PK sample was collected pre-dose at each visit |
| PK Parameter of Benralizumab (Cmax) | First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28) | PK parameters are derived in patients with at least three qualifiable serum PK concentrations post first dose (collected on Day 3, 7, and either 14, or 28) |
| Anti-drug Antibody Responses | From first IP dose to end of treatment period (Day 84) | Anti-drug antibody responses at baseline and post baseline, including nAb responses |
Countries
Chile, Germany, Hungary, Philippines, South Korea, United States
Participant flow
Pre-assignment details
233 participants were randomized to receive treatment in study D3250C00038 (Solana) with benralizumab 30 mg or placebo. Of the 233 patients randomised, all (100.0%) received treatment with study drug. 118 (50.6%) patients received benralizumab 30 mg and 115 (49.4%) patients received placebo.
Participants by arm
| Arm | Count |
|---|---|
| Benra 30 mg 12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days). | 118 |
| Placebo 12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days). | 115 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Benra 30 mg |
|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 12.34 | 51.4 years STANDARD_DEVIATION 12.99 | 51.9 years STANDARD_DEVIATION 13.62 |
| Race/Ethnicity, Customized Asian | 40 Participants | 79 Participants | 39 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 67 Participants | 136 Participants | 69 Participants |
| Sex: Female, Male Female | 83 Participants | 157 Participants | 74 Participants |
| Sex: Female, Male Male | 32 Participants | 76 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 118 | 0 / 115 |
| other Total, other adverse events | 28 / 118 | 30 / 115 |
| serious Total, serious adverse events | 1 / 118 | 7 / 115 |
Outcome results
Primary
Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1
The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 28 | 0.21 Liter | Standard Deviation 0.335 |
| Benra 30 mg | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 56 | 0.22 Liter | Standard Deviation 0.367 |
| Benra 30 mg | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 84 | 0.209 Liter | Standard Deviation 0.344 |
| Placebo | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 28 | 0.132 Liter | Standard Deviation 0.316 |
| Placebo | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 56 | 0.203 Liter | Standard Deviation 0.349 |
| Placebo | Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 | Day 84 | 0.149 Liter | Standard Deviation 0.366 |
p-value: 0.070795% CI: [-0.007, 0.161]Mixed Models Analysis
p-value: 0.774795% CI: [-0.077, 0.104]Mixed Models Analysis
p-value: 0.096995% CI: [-0.014, 0.173]Mixed Models Analysis
p-value: 0.155895% CI: [-0.022, 0.135]Mixed Models Analysis
Primary
Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV)
Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV) | -0.415 Liter | Standard Deviation 0.609 |
| Placebo | Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV) | -0.208 Liter | Standard Deviation 0.528 |
p-value: 0.284795% CI: [-0.505, 0.153]Mixed Models Analysis
Secondary
Change From Baseline 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: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Change From Baseline in ACQ-6 | Day 14 | -0.989 Score on a scale | Standard Deviation 0.901 |
| Benra 30 mg | Change From Baseline in ACQ-6 | Day 28 | -1.126 Score on a scale | Standard Deviation 0.947 |
| Benra 30 mg | Change From Baseline in ACQ-6 | Day 56 | -1.164 Score on a scale | Standard Deviation 1.132 |
| Benra 30 mg | Change From Baseline in ACQ-6 | Day 84 | -1.355 Score on a scale | Standard Deviation 1.146 |
| Placebo | Change From Baseline in ACQ-6 | Day 84 | -0.867 Score on a scale | Standard Deviation 1.114 |
| Placebo | Change From Baseline in ACQ-6 | Day 14 | -0.665 Score on a scale | Standard Deviation 0.837 |
| Placebo | Change From Baseline in ACQ-6 | Day 56 | -0.827 Score on a scale | Standard Deviation 1.023 |
| Placebo | Change From Baseline in ACQ-6 | Day 28 | -0.693 Score on a scale | Standard Deviation 0.869 |
p-value: 0.002495% CI: [-0.481, -0.105]Mixed Models Analysis
p-value: 0.000295% CI: [-0.609, -0.195]Mixed Models Analysis
p-value: 0.011795% CI: [-0.554, -0.07]Mixed Models Analysis
p-value: 0.000495% CI: [-0.731, -0.213]Mixed Models Analysis
p-value: 0.000295% CI: [-0.603, -0.188]Mixed Models Analysis
Secondary
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)
The SGRQ is designed to measure health impairment in patients with asthma and COPD. It contains two parts: Part 1 (Questions 1 to 8) covers the patients' recollection of their symptoms over a preceding 4 weeks; Part 2, 42 items, relates to the daily activity and psychosocial impacts of the individual's respiratory condition. Total score is presented as a percentage of overall impairment, in which 100 represents the worst possible health status, while 0 indicates the best.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 28 | -16.956 Score on a scale | Standard Deviation 15.51 |
| Benra 30 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 56 | -19.941 Score on a scale | Standard Deviation 21.528 |
| Benra 30 mg | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 84 | -23.343 Score on a scale | Standard Deviation 20.302 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 28 | -9.444 Score on a scale | Standard Deviation 14.136 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 56 | -13.802 Score on a scale | Standard Deviation 16.705 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) | Day 84 | -14.385 Score on a scale | Standard Deviation 18.836 |
p-value: 0.000195% CI: [-10.832, -3.626]Mixed Models Analysis
p-value: 0.011595% CI: [-10.538, -1.346]Mixed Models Analysis
p-value: 0.000495% CI: [-13.3, -3.898]Mixed Models Analysis
p-value: 0.000395% CI: [-11.133, -3.38]Mixed Models Analysis
Secondary
Change From Baseline to End of Treatment in FeNO
Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in FeNO | 5.92 ppb | Standard Deviation 45.295 |
| Placebo | Change From Baseline to End of Treatment in FeNO | 0.05 ppb | Standard Deviation 27.634 |
p-value: 0.282595% CI: [-4.492, 15.321]Mixed Models Analysis
Secondary
Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients | -0.394 Liter | Standard Deviation 0.783 |
| Placebo | Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients | 0.093 Liter | Standard Deviation 0.466 |
Secondary
Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients | 0.119 Liter | Standard Deviation 0.447 |
| Placebo | Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients | -0.268 Liter | Standard Deviation 0.603 |
Secondary
Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients | -0.05 ratio | Standard Deviation 0.056 |
| Placebo | Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients | -0.026 ratio | Standard Deviation 0.087 |
Secondary
Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients | -0.276 Liter | Standard Deviation 0.677 |
| Placebo | Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients | -0.175 Liter | Standard Deviation 0.418 |
Secondary
Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients | 0.139 Liter | Standard Deviation 0.245 |
| Placebo | Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients | 0.033 Liter | Standard Deviation 0.676 |
Secondary
Change From Baseline to Post Baseline for Pre-BD FVC
Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 3 | 0.122 Liter | Standard Deviation 0.247 |
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 7 | 0.138 Liter | Standard Deviation 0.277 |
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 14 | 0.126 Liter | Standard Deviation 0.331 |
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 28 | 0.21 Liter | Standard Deviation 0.347 |
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 56 | 0.211 Liter | Standard Deviation 0.404 |
| Benra 30 mg | Change From Baseline to Post Baseline for Pre-BD FVC | Day 84 | 0.213 Liter | Standard Deviation 0.376 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 56 | 0.187 Liter | Standard Deviation 0.369 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 3 | 0.11 Liter | Standard Deviation 0.267 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 28 | 0.134 Liter | Standard Deviation 0.34 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 7 | 0.099 Liter | Standard Deviation 0.292 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 84 | 0.131 Liter | Standard Deviation 0.359 |
| Placebo | Change From Baseline to Post Baseline for Pre-BD FVC | Day 14 | 0.111 Liter | Standard Deviation 0.312 |
p-value: 0.866795% CI: [-0.062, 0.073]Mixed Models Analysis
p-value: 0.273495% CI: [-0.033, 0.115]Mixed Models Analysis
p-value: 0.725295% CI: [-0.068, 0.098]Mixed Models Analysis
p-value: 0.097695% CI: [-0.014, 0.164]Mixed Models Analysis
p-value: 0.653695% CI: [-0.077, 0.122]Mixed Models Analysis
p-value: 0.059595% CI: [-0.004, 0.188]Mixed Models Analysis
p-value: 0.137795% CI: [-0.02, 0.147]Mixed Models Analysis
Secondary
Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1
Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, Day 84. \[Note: Day 28, 56, 84 are presented in the Primary measure.\]
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 7 | 0.125 Liter | Standard Deviation 0.229 |
| Benra 30 mg | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 3 | 0.104 Liter | Standard Deviation 0.223 |
| Benra 30 mg | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 14 | 0.126 Liter | Standard Deviation 0.3 |
| Placebo | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 3 | 0.081 Liter | Standard Deviation 0.269 |
| Placebo | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 7 | 0.081 Liter | Standard Deviation 0.263 |
| Placebo | Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 | Day 14 | 0.1 Liter | Standard Deviation 0.287 |
p-value: 0.638495% CI: [-0.049, 0.08]Mixed Models Analysis
p-value: 0.14895% CI: [-0.016, 0.109]Mixed Models Analysis
p-value: 0.495995% CI: [-0.049, 0.101]Mixed Models Analysis
Secondary
Duration of IP Administration
Duration of IP administration is last IP dose date - first IP dose +1.
Time frame: From first IP to last IP
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Duration of IP Administration | 55.9 Days | Standard Deviation 7.83 |
| Placebo | Duration of IP Administration | 56.2 Days | Standard Deviation 7.61 |
Secondary
Percentage of Pre-BD FEV1 Responder
Pre-BD FEV1 responder is defined as change from baseline in FEV1 \>=100 ml
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 3 | 48.2 Percentage of Participants |
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 7 | 48.3 Percentage of Participants |
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 14 | 50.0 Percentage of Participants |
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 28 | 57.6 Percentage of Participants |
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 56 | 62.1 Percentage of Participants |
| Benra 30 mg | Percentage of Pre-BD FEV1 Responder | Day 84 | 57.9 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 56 | 55.8 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 3 | 37.4 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 28 | 46.9 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 7 | 42.0 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 84 | 51.8 Percentage of Participants |
| Placebo | Percentage of Pre-BD FEV1 Responder | Day 14 | 38.9 Percentage of Participants |
p-value: 0.160495% CI: [0.85, 2.58]Regression, Logistic
p-value: 0.3495% CI: [0.76, 2.19]Regression, Logistic
p-value: 0.092495% CI: [0.93, 2.7]Regression, Logistic
p-value: 0.105295% CI: [0.91, 2.71]Regression, Logistic
p-value: 0.327195% CI: [0.77, 2.21]Regression, Logistic
p-value: 0.301795% CI: [0.77, 2.29]Regression, Logistic
Secondary
Percent Change From Baseline to End of Treatment in Eosinophils Counts
Percent change from baseline to Day 84
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Benra 30 mg | Percent Change From Baseline to End of Treatment in Eosinophils Counts | -88.55 Percent change |
| Placebo | Percent Change From Baseline to End of Treatment in Eosinophils Counts | 11.55 Percent change |
p-value: <0.000195% CI: [-118.9, -83.06]Mixed Models Analysis
Other Pre-specified
Anti-drug Antibody Responses
Anti-drug antibody responses at baseline and post baseline, including nAb responses
Time frame: From first IP dose to end of treatment period (Day 84)
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benra 30 mg | Anti-drug Antibody Responses | nAb prevalence | 2 Participants |
| Benra 30 mg | Anti-drug Antibody Responses | Only post baseline positive | 5 Participants |
| Benra 30 mg | Anti-drug Antibody Responses | Both baseline and post baseline positive | 1 Participants |
| Benra 30 mg | Anti-drug Antibody Responses | Only baseline positive | 1 Participants |
| Benra 30 mg | Anti-drug Antibody Responses | ADA prevalence | 7 Participants |
| Placebo | Anti-drug Antibody Responses | Only baseline positive | 0 Participants |
| Placebo | Anti-drug Antibody Responses | ADA prevalence | 2 Participants |
| Placebo | Anti-drug Antibody Responses | nAb prevalence | 0 Participants |
| Placebo | Anti-drug Antibody Responses | Both baseline and post baseline positive | 2 Participants |
| Placebo | Anti-drug Antibody Responses | Only post baseline positive | 0 Participants |
Other Pre-specified
Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients | -0.233 kPa/L/sec | Standard Deviation 1.509 |
| Placebo | Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients | -0.2 kPa/L/sec | Standard Deviation 0.532 |
Other Pre-specified
Change From Baseline to End of Treatment in CGI-C
Clinician global impression of change (CGI-C) is used for an overall evaluation of response to treatment. The investigator is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Very much improved | 18 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Much improved | 39 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Minimally improved | 39 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | No change | 17 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Minimally worse | 0 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Much worse | 0 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Very much worse | 0 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in CGI-C | Missing | 5 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Missing | 5 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Very much improved | 10 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Minimally worse | 7 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Much improved | 36 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Very much worse | 0 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Minimally improved | 28 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | Much worse | 1 Participants |
| Placebo | Change From Baseline to End of Treatment in CGI-C | No change | 28 Participants |
Comparison: Responder analysis: responder is defined as Very much improved, improved, and minimally improved.p-value: 0.001895% CI: [1.5, 5.88]Regression, Logistic
Other Pre-specified
Change From Baseline to End of Treatment in PGI-C
Patient global impression of change (PGI-C) is used for an overall evaluation of response to treatment. The patient is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Very much improved | 32 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Much improved | 42 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Minimally improved | 23 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | No change | 14 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Minimally worse | 1 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Much worse | 1 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Very much worse | 1 Participants |
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-C | Missing | 4 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Missing | 2 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Very much improved | 17 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Minimally worse | 4 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Much improved | 35 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Very much worse | 0 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Minimally improved | 29 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | Much worse | 1 Participants |
| Placebo | Change From Baseline to End of Treatment in PGI-C | No change | 27 Participants |
Comparison: Responder analysis: responder is defined as Very much improved, improved, and minimally improved.p-value: 0.010795% CI: [1.24, 5.09]Regression, Logistic
Other Pre-specified
Change From Baseline to End of Treatment in PGI-S
The patient global impression of severity (PGI-S) is a single item designed to capture the patient's perception of overall symptom severity at the time of the completion using a 6-point categorical response scale (no symptom \[0\] to very severe symptom \[5\])
Time frame: From first IP dose to Day 84
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in PGI-S | -1.2 Score on a scale | Standard Deviation 1.31 |
| Placebo | Change From Baseline to End of Treatment in PGI-S | -0.8 Score on a scale | Standard Deviation 1.21 |
p-value: 0.01295% CI: [-0.649, -0.081]Mixed Models Analysis
Other Pre-specified
Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients
Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time frame: From first IP dose to Day 84
Population: Body plethysmography sub-study analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients | -0.05 1/(kPa*sec) | Standard Deviation 0.146 |
| Placebo | Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients | 0.052 1/(kPa*sec) | Standard Deviation 0.224 |
Other Pre-specified
PK Parameter of Benralizumab (Cmax)
PK parameters are derived in patients with at least three qualifiable serum PK concentrations post first dose (collected on Day 3, 7, and either 14, or 28)
Time frame: First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28)
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Benra 30 mg | PK Parameter of Benralizumab (Cmax) | 1729.6 ng/mL | Geometric Coefficient of Variation 36.8 |
Other Pre-specified
Serum Concentration of Benralizumab
PK sample was collected pre-dose at each visit
Time frame: From first dose to end of treatment period (Day 84)
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Benra 30 mg | Serum Concentration of Benralizumab | Baseline | 1.95 ng/mL | — |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 3 | 1266.78 ng/mL | Geometric Coefficient of Variation 199.59 |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 7 | 1449.47 ng/mL | Geometric Coefficient of Variation 125.02 |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 14 | 1317.92 ng/mL | Geometric Coefficient of Variation 79.53 |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 28 | 738.47 ng/mL | Geometric Coefficient of Variation 80.77 |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 56 | 1015.72 ng/mL | Geometric Coefficient of Variation 59.74 |
| Benra 30 mg | Serum Concentration of Benralizumab | Day 84 | 1079.22 ng/mL | Geometric Coefficient of Variation 73.24 |