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

Study Overview
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Brief Summary
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Phase 3 study to evaluate the efficacy and safety of a benralizumab in patients with moderate to very severe COPD with a history of frequent COPD exacerbations and elevated peripheral blood eosinophils (≥300/μL). Eligible patients must have a history of ≥2 moderate and/or severe COPD exacerbations in the previous year despite receiving triple (ICS/LABA/LAMA) background therapy for at least 3 months and ICS-based dual inhaled treatment for the remainder of the year. Eligible patients must also have an elevated blood eosinophil count. The treatment period will be of variable duration and will continue until the last patient has the opportunity to complete a minimum of 56 weeks, at which point all patients will complete the study. The primary endpoint will be analyzed at Week 56.

Official Title
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A Multicenter, Randomized, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab 100 mg in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With a History of Frequent COPD Exacerbations and Elevated Peripheral Blood Eosinophils (RESOLUTE)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent Age 40 to 85 years Male and/or female. Current or former smoker with a tobacco history of ≥10 pack-years. History of moderate to very severe COPD with a post-bronchodilator FEV1/FVC<0.70 and FEV1 ≤65% of predicted normal value. Documented history of 2 or more COPD exacerbations that required treatment with systemic corticosteroids and/or hospitalization within 52 weeks prior to enrollment. Exacerbations treated with antibiotics alone are excluded unless accompanied by treatment with systemic corticosteroids and/or hospitalization. Hospitalization is defined as an inpatient admission ≥24 hours Previous exacerbations should be confirmed to have occurred while on stable triple therapy for COPD. At least one qualifying COPD exacerbation should occur while on stable uninterrupted triple therapy prior to enrolment. Documented use of triple (ICS/LABA/LAMA) background therapy for COPD for ≥3 months immediately prior to enrollment. Treatment with at least double inhaled therapy containing ICS (e.g. ICS/LABA or ICS/LAMA) for the remaining of 52 weeks prior to enrolment. Use of LABA/LAMA is allowed if ICS cannot be tolerated. ICS in a dose approved for COPD or equivalent to ≥250 mcg of fluticasone propionate daily. Total cumulative duration of not being on double or triple background therapy must not exceed 2 months. Stable therapy/doses for the last 3 months prior to randomization. Blood eosinophil count ≥300/μL at screening and documented historical eosinophil count of ≥150/μL within 52 weeks of enrollment (or repeated testing during run-in). CAT total score ≥15 at Visit 1. Negative pregnancy test for females of childbearing potential (WOCBP) at Visit 1. Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control from enrollment throughout the study and within 12 weeks after last dose of IP. Women not of childbearing potential are defined as women who are either permanently sterilized or postmenopausal (confirmed by FSH test for women <50 years). Exclusion Criteria: Clinically important pulmonary disease other than COPD Current diagnosis of asthma, prior history of asthma or asthma-COPD overlap according to GINA/GOLD. Childhood history of asthma is allowed and defined as asthma diagnosed and resolved before the age of 18. Radiological findings of a respiratory disease other than COPD contributing to respiratory symptoms. Solitary pulmonary nodules without appropriate follow up or findings of acute infection. Another pulmonary or systemic disease associated with elevated peripheral eosinophil counts. Any unstable disorder that could affect patient safety, study findings or the patient's ability to complete the study. Any clinically significant abnormal findings in physical examination, vital signs, ECG, laboratory tests could affect patient safety, study findings or the patient's ability to complete the study. Cor pulmonale and/or right ventricular failure. Long-term treatment with oxygen >4.0 L/min and/or oxyhemoglobin saturation <89% while breathing supplemental oxygen. Use of any non-invasive positive pressure ventilation device (NIPPV). Note: use of CPAP for Sleep Apnea Syndrome is allowed. Known immunodeficiency disorder, including positive HIV-1/2 testing. Active liver disease. Chronic stable hepatitis B and C (including positive HBsAg or hepatitis C antibody testing), or other stable chronic liver disease are acceptable. ALT or AST ≥3 times the upper limit of normal, confirmed by repeated testing during the run-in period. Helminth parasitic infection within 24 weeks prior to enrollment, not treated or failed to respond to standard of care therapy. Alcohol or drug abuse within the past year, which may compromise the study data. Malignancy, current or within the past 5 years, except for adequately treated non invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1. Suspected malignancy or undefined neoplasms. Evidence of active tuberculosis, as judged by investigator. Patients with a recent (within 2 years) first-time or newly positive PPD or Quantiferon test need to complete an appropriate course of treatment before enrollment. Evaluation will be according to the local standard of care. Participation, or planned participation, in intensive COPD rehabilitation program (maintenance phase of a rehabilitation is allowed). History of surgical or endoscopic lung volume reduction within the 6 months prior to enrollment. History of partial or total lung resection (single lobe or segmentectomy is acceptable). Scheduled major surgical procedure during the study. Minor elective procedures are allowed. History of anaphylaxis to any biologic therapy or vaccine. Receipt of blood products or immunoglobulins within 30 days prior to randomization. Receipt of marketed or investigational biologic product within 4 months or 5 half-lives prior to randomization, whichever is longer. Exception: Patients on stable therapy for 3 months before randomization who intend to stay on treatment throughout the study with marketed biologic products that are not likely to interfere with the safety assessment and/or efficacy of benralizumab, for example, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases, can participate in the study. Receipt of live attenuated vaccines 30 days prior to randomization. Chronic use of immunosuppressive medication or expected need for chronic use during the study. Chronic use of antibiotics if duration of treatment is <9 months prior to randomization. Chronic macrolide or other antibiotic therapy is allowed provided the patient has been on stable dose/regimen for ≥9 months prior to randomization and has had ≥2 COPD exacerbations while on stable therapy. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment. Receipt of benralizumab within 12 months prior to enrollment. Known history of allergy or reaction to any component of the IP formulation.

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<br>Administrated subcutaneously (SC) every 4 weeks for the first 3 doses, then every 8 weeks | Biological: Benralizumab<br>* Benralizumab solution for injection in accessorized prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks until the end of treatment.<br>|
| Placebo Comparator: Placebo<br>Administrated subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks | Biological: Placebo<br>* Matching placebo will be administered subcutaneously with accessorized prefilled syringe (APFS) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks until the end of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of moderate or severe COPD exacerbations | Moderate or severe COPD exacerbation is defined by symptomatic worsening of COPD requiring: Use of systemic corticosteroids for at least 3 days; and/or Use of antibiotics; and/or An inpatient hospitalization or death due to COPD | Over first 56 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of severe COPD exacerbations | A severe COPD exacerbation is defined by symptomatic worsening of COPD requiring an inpatient hospitalization or results in death due to COPD | Minimum of 1 year and an average of 2 years | 
| Annualized rate of COPD exacerbations that are associated with an emergency room/emergency department visit or a hospitalization |  | Minimum of 1 year and an average of 2 years | 
| Time to first COPD exacerbation |  | During first 56 weeks | 
| Change from baseline in SGRQ total and domain scores | St. George's Respiratory Questionnaire (SGRQ) | up to 56 weeks | 
| Change from baseline in E-RS:COPD total and domain scores | Evaluating Respiratory Symptoms in COPD (E-RS:COPD) | up to 56 weeks | 
| Change from baseline in pre-dose/pre-bronchodilator FEV1 | FEV1 is the Forced expiratory volume in one second at study site | up to 56 weeks | 
| All cause and respiratory-related mortality rate |  | Minimum of 1 year and an average of 2 years | 
| Annual rate of hospitalizations due to COPD |  | Minimum of 1 year and an average of 2 years | 
| Serum benralizumab concentration as a measure of pharmacokinetics |  | up to 56 weeks | 
| Anti-drug antibodies (ADA) as a measure of immunogenicity |  | up to 56 weeks | 
| Change from baseline in CAT total score | Chronic Obstructive Pulmonary Disease assessment tool (CAT) | up to 56 weeks | 
| Length of hospital stay |  | Minimum of 1 year and an average of 2 years | 
| ICU (Intensive Care Unit) days |  | Minimum of 1 year and an average of 2 years | 
| Annual rate of hospitalizations and emergency department visits combined |  | Minimum of 1 year and an average of 2 years | 
| Annual rate of unscheduled outpatient visits including unscheduled visits to study sites |  | Minimum of 1 year and an average of 2 years | 
| Annual rate of unscheduled healthcare encounters |  | Minimum of 1 year and and average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICS, Chronic Obstructive Pulmonary Disease, COPD, benralizumab, Fasenra, inhaled corticosteroids, exacerbations, Lung Disease, LABA/LAMA