Moderate to Very Severe Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Obstructive Lung Diseases, Chronic Obstructive Pulmonary Disease, Lung Disease, Bronchial Diseases, COPD Exacerbation, Respiratory Tract Diseases
Brief summary
The purpose of the study is to determine if benralizumab reduces COPD exacerbation rate in symptomatic patients with moderate to very severe COPD who are receiving standard of care therapies
Interventions
Benralizumab subcutaneously on study week 0 until study week 48 inclusive
Benralizumab subcutaneously on study week 0 until study week 48 inclusive
DRUGPlacebo
Placebo subcutaneously on study week 0 until study week 48 inclusive
Sponsors
MedImmune LLC
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1.Informed consent. 2.Subjects 40-85 y.o. 3.Moderate to very severe COPD with Post Bronchodilator (BD) FEV1\>20% and ≤65%. 4.≥2 moderate or ≥1 severe COPD exacerbation(s) required treatment or hospitalization within 2-52 weeks prior to Visit1. 5. Modified Medical Research Council (mMRC) score ≥1 at Visit 1. 6.Treatment with double or triple therapy throughout the year prior to Visit 1, constant 2 weeks prior to Visit 1. 7.Tobacco history of ≥10 pack-years. 8.Women of childbearing potential must use a highly effective form of birth control from Visit 1 until 16 weeks after their last dose, and negative serum pregnancy test result at Visit 1. 9.Male subjects who are sexually active must be surgically sterile one year prior to Visit 1 or use an adequate method of contraception from the first Investigational Product (IP) dose until 16 weeks after their last dose. 10.Compliance with maintenance therapy during run-in ≥70%. 11. Blood eosinophils due to subject's stratification and cap for blood eosinophil levels.When any eosinophil cohort is full, subjects in the completed cohort will not be randomised and will be withdrawn from the study.
Exclusion criteria
1. Clinically important pulmonary disease other than COPD or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts. 2\. Any disorder or major physical impairment that is not stable by Investigator opinion and/or could affect: - subject safety-study findings or their interpretation or subject's ability to complete the entire study duration. 3\. Unstable ischemic heart disease, arrhythmia, cardiomyopathy, or other relevant cardiovascular disorder that in Investigator's judgment may put the patient at risk or negatively affect the study outcome. 4\. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 2 weeks prior to Visit1 or during the enrolment and run-in period. 5\. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 2 weeks prior to Visit1or during the enrolment and run-in period. 6\. Pneumonia within 8 weeks prior to Visit1 or during the enrolment and run-in period. 7\. Pregnant, breastfeeding, or lactating women. 8. Risk factors for pneumonia 9. History of anaphylaxis to any other biologic therapy. 10. Long term oxygen therapy with signs and/or symptoms of cor pulmonale, right ventricular failure. 11\. Use of immunosuppressive medication within 2 weeks prior to Visit1 and/or during the enrolment and run-in period. 12\. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to Visit 1. 13\. Evidence of active tuberculosis (TB) without an appropriate course of treatment. 14\. Lung volume reduction surgery within the 6 months prior to Visit 1. History of partial or total lung resection (single lobe or segmentectomy is acceptable). 15\. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines or other accepted guidelines. 16\. Previous treatment with benralizumab. 17. Helminth parasitic infection diagnosed within 24 weeks prior to Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | From first IP to week 56 | A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL | From first IP to week 56 | A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model. |
| Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL | First IP up to Week 56 | SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status. |
| Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL | First IP up to Week 56 | CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status. |
| Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL | First IP up to Week 56 | The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity. |
| Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL | First IP up to Week 56 | The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use. |
| Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL | First IP up to Week 56 | Change from baseline to week 56 in proportion of nights awakenings due to respiratory symptoms. |
| Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Exacerbation event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an exacerbation event has occurred. |
| Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Severity for the study is the highest score of EXACT-PRO. |
| Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL | First IP up to end of treatment Week 56 | Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment. |
| Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Annual EXACT-PRO exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model. |
| Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD. |
| Time to First COPD Exacerbation | Immediately following first IP up to week 56 | Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation |
| Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | Annual COPD exacerbations rate that result in ER or hospitalization is calculated by number of exacerbations resulting ER or hospitalization divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model. |
| Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports. |
| Duration of Study Treatment Administration | From first dose date to last dose date, 48 weeks per protocol. | Duration of study treatment is calculated from first dose date to last dose date + 1 day. |
| Serum Concentration of Benralizumab | Pre-first dose and pre-dose at end of treatment (week 56) | PK serum samples were collected pre-dose at each visit. |
| Immunogenicity of Benralizumab | Pre-treatment until end of follow-up, week 60 per protocol. | Antidrug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented |
| Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL | Immediately following first IP up to week 56 | The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery. That is, duration of the exacerbation is the time elapse between onset and recovery of the event. |
Countries
Austria, Canada, Czechia, Germany, Hungary, Italy, Japan, Netherlands, Poland, Romania, Russia, South Africa, South Korea, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
1656 patients randomized to Benralizumab 30 mg, Benralizumab 100 mg, or Placebo. All randomized patients were treated. 554 (33.5%) were randomized to Benralizumab 30 mg, 552 (33.3%) were randomized to Benralizumab 100 mg, and 550 (33.2%) were randomized to Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Benralizumab 30 mg Every 8 weeks administered subcutaneously | 554 |
| Benralizumab 100 mg Every 8 weeks administered subcutaneously | 552 |
| Placebo Every 8 weeks administered subcutaneously | 550 |
| Total | 1,656 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 | 3 |
| Overall Study | Death | 14 | 11 | 12 |
| Overall Study | eg., meds change, lack of efficacy, etc. | 6 | 9 | 7 |
| Overall Study | incorrect enrolment | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 2 | 3 |
| Overall Study | Severe non-compliance | 1 | 2 | 1 |
| Overall Study | Study specific withdrawal criteria | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 27 | 31 | 32 |
Baseline characteristics
| Characteristic | Placebo | Total | Benralizumab 30 mg | Benralizumab 100 mg |
|---|---|---|---|---|
| Age, Continuous | 65.2 Year STANDARD_DEVIATION 8.22 | 65.5 Year STANDARD_DEVIATION 8.01 | 65.9 Year STANDARD_DEVIATION 7.77 | 65.3 Year STANDARD_DEVIATION 8.05 |
| Race/Ethnicity, Customized Asian | 46 Participants | 140 Participants | 48 Participants | 46 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 25 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 14 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 488 Participants | 1477 Participants | 496 Participants | 493 Participants |
| Sex: Female, Male Female | 175 Participants | 527 Participants | 172 Participants | 180 Participants |
| Sex: Female, Male Male | 375 Participants | 1129 Participants | 382 Participants | 372 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 554 | 11 / 552 | 13 / 550 |
| other Total, other adverse events | 293 / 554 | 318 / 552 | 282 / 550 |
| serious Total, serious adverse events | 151 / 554 | 177 / 552 | 176 / 550 |
Outcome results
Primary
Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL
A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time frame: From first IP to week 56
Population: Full analysis set with baseline EOS\>=220/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.19 Exacerbations per year |
| Benralizumab 100 mg | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.03 Exacerbations per year |
| Placebo | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.24 Exacerbations per year |
p-value: 0.64995% CI: [0.8, 1.15]Negative binomial
p-value: 0.052595% CI: [0.69, 1]Negative binomial
Secondary
Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL
Annual COPD exacerbations rate that result in ER or hospitalization is calculated by number of exacerbations resulting ER or hospitalization divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 0.27 Exacerbations per year |
| Benralizumab 100 mg | Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 0.15 Exacerbations per year |
| Placebo | Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 0.25 Exacerbations per year |
p-value: 0.773395% CI: [0.73, 1.53]Negative binomial
p-value: 0.011495% CI: [0.39, 0.89]Nagative binomial
Secondary
Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL
A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time frame: From first IP to week 56
Population: Full analysis set with baseline EOS\<220/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL | 1.4 Exacerbations per year |
| Benralizumab 100 mg | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL | 1.32 Exacerbations per year |
| Placebo | Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL | 1.30 Exacerbations per year |
p-value: 0.523695% CI: [0.86, 1.34]Negative binomial
p-value: 0.881295% CI: [0.82, 1.27]Negative binomial
Secondary
Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Annual EXACT-PRO exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Benralizumab 30 mg | Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.14 Exacerbations per year |
| Benralizumab 100 mg | Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.02 Exacerbations per year |
| Placebo | Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL | 1.04 Exacerbations per year |
p-value: 0.40895% CI: [0.89, 1.34]Negative binomial
p-value: 0.868895% CI: [0.8, 1.21]Negative binomial
Secondary
Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery. That is, duration of the exacerbation is the time elapse between onset and recovery of the event.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL | 82.2 Days | Standard Deviation 95.8 |
| Benralizumab 100 mg | Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL | 88.3 Days | Standard Deviation 105.3 |
| Placebo | Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL | 101.7 Days | Standard Deviation 113.7 |
Secondary
Duration of Study Treatment Administration
Duration of study treatment is calculated from first dose date to last dose date + 1 day.
Time frame: From first dose date to last dose date, 48 weeks per protocol.
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Duration of Study Treatment Administration | 302.4 Days | Standard Deviation 85.73 |
| Benralizumab 100 mg | Duration of Study Treatment Administration | 304.0 Days | Standard Deviation 82.4 |
| Placebo | Duration of Study Treatment Administration | 302.5 Days | Standard Deviation 88.47 |
Secondary
Immunogenicity of Benralizumab
Antidrug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented
Time frame: Pre-treatment until end of follow-up, week 60 per protocol.
Population: safety analysis set. For each parameter, the number of subjects at risk is to be analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg | Immunogenicity of Benralizumab | Only post baseline positive | 43 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | ADA prevalence | 53 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | ADA transiently positive | 15 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | Only baseline positive | 5 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | ADA persistently positive | 28 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | nAb incidence | 41 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | Both base/post-baseline positive | 5 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | ADA incidence | 44 Participants |
| Benralizumab 30 mg | Immunogenicity of Benralizumab | nAb prevalence | 43 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | Only baseline positive | 11 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | ADA prevalence | 64 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | ADA incidence | 47 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | Both base/post-baseline positive | 7 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | Only post baseline positive | 46 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | ADA persistently positive | 34 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | nAb incidence | 37 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | ADA transiently positive | 12 Participants |
| Benralizumab 100 mg | Immunogenicity of Benralizumab | nAb prevalence | 43 Participants |
| Placebo | Immunogenicity of Benralizumab | nAb incidence | 18 Participants |
| Placebo | Immunogenicity of Benralizumab | ADA persistently positive | 14 Participants |
| Placebo | Immunogenicity of Benralizumab | Only post baseline positive | 20 Participants |
| Placebo | Immunogenicity of Benralizumab | nAb prevalence | 25 Participants |
| Placebo | Immunogenicity of Benralizumab | ADA transiently positive | 6 Participants |
| Placebo | Immunogenicity of Benralizumab | Only baseline positive | 2 Participants |
| Placebo | Immunogenicity of Benralizumab | ADA prevalence | 39 Participants |
| Placebo | Immunogenicity of Benralizumab | Both base/post-baseline positive | 17 Participants |
| Placebo | Immunogenicity of Benralizumab | ADA incidence | 24 Participants |
Secondary
Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL
CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status.
Time frame: First IP up to Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL | -1.50 Score on a scale | Standard Deviation 6.89 |
| Benralizumab 100 mg | Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL | -2.43 Score on a scale | Standard Deviation 6.34 |
| Placebo | Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL | -1.22 Score on a scale | Standard Deviation 6.53 |
p-value: 0.678295% CI: [-1.08, 0.7]Mixed Models Analysis
p-value: 0.075395% CI: [-1.7, 0.08]Mixed Models Analysis
Secondary
Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL
The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.
Time frame: First IP up to Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL | -1.085 Score on a scale | Standard Deviation 5.273 |
| Benralizumab 100 mg | Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL | -1.354 Score on a scale | Standard Deviation 5.599 |
| Placebo | Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL | -0.504 Score on a scale | Standard Deviation 5.674 |
p-value: 0.088995% CI: [-1.26, 0.089]Mixed Models Analysis
p-value: 0.041395% CI: [-1.378, -0.028]Mixed Models Analysis
Secondary
Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL
Change from baseline to week 56 in proportion of nights awakenings due to respiratory symptoms.
Time frame: First IP up to Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL | -0.088 Proportion of nights | Standard Deviation 0.31 |
| Benralizumab 100 mg | Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL | -0085 Proportion of nights | Standard Deviation 0.283 |
| Placebo | Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL | -0.049 Proportion of nights | Standard Deviation 0.307 |
p-value: 0.023595% CI: [-0.077, -0.006]Mixed Models Analysis
p-value: 0.015895% CI: [-0.08, -0.008]Mixed Models Analysis
Secondary
Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL
SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status.
Time frame: First IP up to Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL | -5.025 Percentage | Standard Deviation 14.677 |
| Benralizumab 100 mg | Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL | -6.723 Percentage | Standard Deviation 15.723 |
| Placebo | Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL | -3.913 Percentage | Standard Deviation 15.039 |
p-value: 0.290695% CI: [-2.887, 0.865]Mixed Models Analysis
p-value: 0.026495% CI: [-4.02, -0.251]Mixed Models Analysis
Secondary
Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL
The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.
Time frame: First IP up to Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL | -0.05 Puffs/day | Standard Deviation 3.21 |
| Benralizumab 100 mg | Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL | -0.27 Puffs/day | Standard Deviation 2.71 |
| Placebo | Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL | 0.29 Puffs/day | Standard Deviation 3.03 |
p-value: 0.072895% CI: [-0.728, 0.032]Mixed Models Analysis
p-value: 0.012195% CI: [-0.868, -0.107]Mixed Models Analysis
Secondary
Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL
Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment.
Time frame: First IP up to end of treatment Week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL | 0.014 Liter | Standard Deviation 0.282 |
| Benralizumab 100 mg | Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL | 0.031 Liter | Standard Deviation 0.294 |
| Placebo | Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL | 0.010 Liter | Standard Deviation 0.275 |
p-value: 0.75595% CI: [-0.035, 0.048]Mixed Models Analysis
p-value: 0.328595% CI: [-0.021, 0.062]Mixed Models Analysis
Secondary
Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Exacerbation event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an exacerbation event has occurred.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, EOS\>=220/uL
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 9 | 1 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 0 | 180 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 3 | 25 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 4 | 17 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 7 | 6 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 2 | 42 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 6 | 4 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 10 | 0 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 1 | 101 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 8 | 1 Participants |
| Benralizumab 30 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 5 | 5 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 2 | 49 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 6 | 4 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 8 | 1 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 7 | 1 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 9 | 2 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 10 | 1 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 5 | 6 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 4 | 13 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 0 | 184 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 1 | 103 Participants |
| Benralizumab 100 mg | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 3 | 14 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 4 | 14 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 8 | 4 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 10 | 0 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 0 | 179 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 1 | 99 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 2 | 34 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 7 | 5 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 3 | 15 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 5 | 5 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 6 | 2 Participants |
| Placebo | Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL | 9 | 1 Participants |
Secondary
Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL
Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Hospitalisations | 60 Participants |
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Emergency Department Visits | 36 Participants |
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Telephone calls | 110 Participants |
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Ambulance transports | 16 Participants |
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Unscheduled Outpatient Visits | 219 Participants |
| Benralizumab 30 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Home Visits | 18 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Ambulance transports | 12 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Hospitalisations | 38 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Telephone calls | 111 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Home Visits | 22 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Emergency Department Visits | 35 Participants |
| Benralizumab 100 mg | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Unscheduled Outpatient Visits | 236 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Home Visits | 18 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Telephone calls | 104 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Unscheduled Outpatient Visits | 202 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Ambulance transports | 20 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Emergency Department Visits | 43 Participants |
| Placebo | Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL | Hospitalisations | 50 Participants |
Secondary
Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL
A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Benralizumab 30 mg | Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL | 204 Participants |
| Benralizumab 100 mg | Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL | 203 Participants |
| Placebo | Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL | 198 Participants |
Comparison: Proportion of participants with \>=1 COPD exacerbation.p-value: 0.48595% CI: [0.66, 1.22]Cochran-Mantel-Haenszel
Comparison: Proportion of participants with \>=1 COPD exacerbation.p-value: 0.448995% CI: [0.65, 1.21]Cochran-Mantel-Haenszel
Secondary
Serum Concentration of Benralizumab
PK serum samples were collected pre-dose at each visit.
Time frame: Pre-first dose and pre-dose at end of treatment (week 56)
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Benralizumab 30 mg | Serum Concentration of Benralizumab | Baseline | NA ng/mL | — |
| Benralizumab 30 mg | Serum Concentration of Benralizumab | Week 56 | 219.45 ng/mL | Geometric Coefficient of Variation 233.21 |
| Benralizumab 100 mg | Serum Concentration of Benralizumab | Baseline | NA ng/mL | — |
| Benralizumab 100 mg | Serum Concentration of Benralizumab | Week 56 | 699.89 ng/mL | Geometric Coefficient of Variation 243.2 |
Secondary
Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Severity for the study is the highest score of EXACT-PRO.
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Benralizumab 30 mg | Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL | 51.5 Score on a scale | Standard Deviation 11.3 |
| Benralizumab 100 mg | Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL | 50.8 Score on a scale | Standard Deviation 10.7 |
| Placebo | Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL | 52.0 Score on a scale | Standard Deviation 11.2 |
Secondary
Time to First COPD Exacerbation
Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation
Time frame: Immediately following first IP up to week 56
Population: Full analysis set, baseline EOS\>=220/uL
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Benralizumab 30 mg | Time to First COPD Exacerbation | 333 Days |
| Benralizumab 100 mg | Time to First COPD Exacerbation | 329 Days |
| Placebo | Time to First COPD Exacerbation | 337 Days |