Efficacy and Safety of Benralizumab in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History

Study Overview
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Brief Summary
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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.

Official Title
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A Randomised, Double-blind, Double Dummy, 56 Week Placebo-controlled, Multicentre, Parallel Group, Phase 3 Study Evaluating Efficacy/Safety of 3 Benralizumab Doses in Patients With Moderate to Very Severe COPD With Previous Exacerbations.

Conditions
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Moderate to Very Severe Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Benralizumab Arm A
* Drug: Benralizumab Arm B
* Drug: Benralizumab Arm C
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:. Informed consent. Subjects 40-85 y.o. Moderate to very severe COPD with Post Bronchodilator (BD) FEV1>20% and ≤65%. -≥2 moderate or ≥1 severe COPD exacerbation(s) required treatment or hospitalization within 2-52 weeks prior to Visit1. Modified Medical Research Council (mMRC) score ≥1 at Visit 1. Treatment with double or triple therapy throughout the year prior to Visit 1, constant 2 weeks prior to Visit 1. Tobacco history of ≥10 pack-years. 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. 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. Compliance with maintenance therapy during run-in ≥70%. 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levels.When any eosinophil cohort is full, subjects in the completed cohort will not be randomised and will be withdrawn from the study.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: Clinically important pulmonary disease other than COPD or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts. 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. 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. 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. Acute upper or lower respiratory infection requiring antibiotics within 2 weeks prior to Visit1 or during the enrolment and run-in period. Pneumonia within 8 weeks prior to Visit1 or during the enrolment and run-in period. Pregnant, breastfeeding, or lactating women. Risk factors for pneumonia History of anaphylaxis to any other biologic therapy. Long term oxygen therapy with signs and/or symptoms of cor pulmonale, right ventricular failure. Use of immunosuppressive medication within 2 weeks prior to Visit1 and/or during the enrolment and run-in period. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to Visit 1. Evidence of active tuberculosis (TB) without an appropriate course of treatment. 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). Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines or other accepted guidelines. Previous treatment with benralizumab. Helminth parasitic infection diagnosed within 24 weeks prior to Visit 1.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab Arm A<br>Benralizumab administered subcutaneously | Drug: Benralizumab Arm A<br>* Benralizumab subcutaneously on study week 0 until study week 48 inclusive<br>|
| Experimental: Benralizumab Arm B<br>Benralizumab administered subcutaneously | Drug: Benralizumab Arm B<br>* Benralizumab subcutaneously on study week 0 until study week 48 inclusive<br>|
| Experimental: Benralizumab Arm C<br>Benralizumab administered subcutaneously | Drug: Benralizumab Arm C<br>* Benralizumab subcutaneously on study week 0 until study week 48 inclusive<br>|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Drug: Placebo<br>* Benralizumab subcutaneously on study week 0 until study week 48 inclusive<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Immediately following the first IP dose through week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Immediately following the first IP dose through week 56 | 
| 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. | First IP up to end of treatment Week 56 | 
| 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. | First IP up to Week 56 | 
| 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. | First IP up to Week 56 | 
| 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. | First IP up to Week 56 | 
| 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. | First IP up to Week 56 | 
| Mean Change From Baseline in Proportion of Nights With Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL | Change from baseline to Week 56 in proportion of nights with awakenings due to respiratory symptoms. | First IP up to Week 56 | 
| 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 considering their experiences today. The daily EXACT-PRO total score is recorded and has a range of 0-100 with higher scores indicative of greater severity. COPD exacerbation event frequency is calculated based on comparison of the baseline score with daily total scores. An increase of EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicates a COPD exacerbation event has occurred. | Immediately following first IP up to week 56 | 
| 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 considering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Severity of the study is the highest score of EXACT-PRO. | Immediately following first IP up to week 56 | 
| Duration of COPD Exacerbation Based on EXACT-PRO Score 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 considering their experiences today. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. COPD exacerbation event frequency is identified by comparing the baseline score 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. Event duration is calculated 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. | Immediately following first IP up to week 56 | 
| 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 considering 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. | Immediately following the first IP dose through week 56 | 
| 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. | Immediately following first IP dose up to week 56 | 
| Time to First COPD Exacerbation | Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation. | Immediately following IP dose to Week 56 | 
| 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. | Immediately following the first IP dose through week 56 | 
| 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. | Immediately following first IP dose up to Week 56 | 
| Duration of Study Treatment Administration | Duration of study treatment is calculated from first dose date to last dose date + 1 day. | From first dose date to last dose date, 48 weeks per protocol. | 
| Serum Concentration of Benralizumab | PK serum samples were collected pre-dose at each visit. | Pre-first dose and pre-dose at end of treatment (week 56). | 
| Immunogenicity of Benralizumab | Anti-drug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented. | Pre-treatment until end of follow-up, week 60 per protocol. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive Lung Diseases, Chronic Obstructive Pulmonary Disease, Lung Disease, Bronchial Diseases, COPD Exacerbation, Respiratory Tract Diseases