Efficacy and Safety of Benralizumab in Patients With Non-cystic Fibrosis Bronchiectasis

Study Overview
=================
Brief Summary
-----------------
This is a multicentre, randomised, double-blind, parallel-group, placebo-controlled, phase III study originally designed to test the hypothesis that benralizumab will reduce exacerbation rates compared with placebo on top of standard-of-care therapy in adult patients with non-cystic fibrosis bronchiectasis with eosinophilic inflammation (NCFB+EI). All patients who complete the double-blind treatment period (28 to 52 weeks depending on the timing of patient randomization and when the revised CSP version 3.0 becomes effective) on investigational product (IP) may be eligible to continue into an open-label extension (OLE) period during which all patients will receive benralizumab. The revised OLE period is intended to allow patients approximately 32 weeks of treatment with open label benralizumab (24 weeks followed by a FU visit 8 weeks after the last dose of IP for a total of approximately 32 weeks).

Official Title
-----------------
A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 52 Week, Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Non-Cystic Fibrosis Bronchiectasis (MAHALE)

Conditions
-----------------
Non-cystic Fibrosis Bronchiectasis

Intervention / Treatment
-----------------
* Biological: Benralizumab
* Biological: Placebo to Benralizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, at least 18 years of age inclusive at the time of signing the ICF Must have NCFB diagnosed by a physician and confirmed by CT (measured at screening; if a new CT is not possible, a CT performed within 12 months of the screening visit is acceptable). Documented history of 2 or more bronchiectasis exacerbations within a year of the screening visit. If receiving prophylactic systemic or inhaled antibiotics to prevent bronchiectasis exacerbations, the dose/regimen must be stable for at least 3 months prior to the screening visit and remain stable throughout the DB period of the study. If prophylactic macrolides have been recently discontinued, patients must have been off treatment for at least 3 months prior to randomisation. In all other cases of prophylactic antibiotic use, ≥ 4 weeks wash out period should be in place after the last dose of antibiotic and prior to randomisation Must be on airway clearance therapy, physiotherapy, or mucus clearance therapy.The dose and regimen of these therapies and any drugs used to aid expectoration should be stable for at least 3 months prior to the screening visit and remain stable throughout the DB period of the study. If receiving inhaled corticosteroid or bronchodilator therapy, the dose and regimen should be stable with no alteration to dose or formulation for at least 3 months prior to the screening visit and this should remain stable throughout the DB period of the study. Women of childbearing potential (WOCBP) must have a negative serum and urine pregnancy test prior to randomization and agree to use a highly effective method of birth control from enrollment, throughout the study duration, and for 12 weeks after the last dose of IP. Exclusion Criteria: Pulmonary disease other than bronchiectasis. Patients with a history of NTM disease may be enrolled if they have completed treatment prior to the Screening visit, if at least 3 months have elapsed since the last day of antibiotic treatment for NTM at the Screening visit, and if they have had a negative sputum culture prior to the screening visit. Another diagnosed or suspected pulmonary or systemic disease associated with elevated peripheral eosinophil counts Respiratory infection or bronchiectasis exacerbation during the screening period. Any other clinical condition that is not stable in the opinion of the Investigator and could: Affect the safety of the patient during the study. Influence the findings of the study or their interpretation. Impede the patient's ability to complete the entire duration of the study. Radiological findings suggestive of a respiratory disease other than bronchiectasis, suggestive of acute infection, or of solitary pulmonary nodules without appropriate follow up and demonstration of stability as per standard of care. Pulmonary nodules > 6 mm in size should have at least 2 years of follow up with no change on CT imaging. Current active liver disease Current malignancy, or history of malignancy, except for: Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to Visit 1 Patients who have had other malignancies are eligible provided that the participant is in remission and curative therapy was completed at least 5 years prior to Visit 1. History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2. History of alcohol or drug abuse within the past year Current smokers with a tobacco history of ≥ 10 pack-years or ex-smoker with a tobacco history of ≥ 10 pack-years. Patients receiving long-term oxygen treatment Patients participating in, or scheduled for, an intensive (active) pulmonary rehabilitation programme. Patients who are in the maintenance phase of a rehabilitation programme are eligible. Use of non-invasive positive-pressure ventilation for conditions other than obstructive sleep apnoea Use of immunosuppressive medication within 3 months of the screening visit or expected need for chronic use (≥ 4 weeks) during study Receipt of any marketed or investigational biologic products (monoclonal or polyclonal antibody) within one year of the screening visit Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to randomisation Receipt of immunoglobulin and blood products within 30 days of the date of the screening visit Receipt of live attenuated vaccines within 30 days of the date of randomisation Concurrent enrolment in another clinical drug interventional trial History of anaphylaxis to any biologic therapy or vaccine Known history of allergy or reaction to any component of the IP formulation. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements Previous randomisation in the present study Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Benralizumab will be administered subcutaneously (SC) using an accessorized prefilled syringe (APFS) | Biological: Benralizumab<br>* Benralizumab active solution in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC), 1 mL fill volume<br>|
| Placebo Comparator: Placebo<br>Matching placebo solution will be administered subcutaneously (SC) using an accessorized prefilled syringe (APFS) | Biological: Placebo to Benralizumab<br>* Matching placebo solution in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC), 1 mL fill volume<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualised exacerbation rate | Annualised exacerbation rate | over the DB treatment period (28 to 52 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first bronchiectasis exacerbation |  | over the DB treatment period (28 to 52 weeks) | 
| Change from baseline in QoL-B-RSS | Quality of Life-Bronchiectasis-Respiratory Symptoms Scale (QoL-B-RSS). QoL-B-RSS evaluates respiratory symptoms using 9 items from the 37-item QoL-B questionnaire. The QoL-B-RSS is standardized from 0 to 100, with higher scores indicative of better health-related quality of life. | over the DB treatment period (28 to 52 weeks) | 
| Change from baseline in pre-dose FEV1 | forced expiratory volume in 1 second (FEV1) | over the DB treatment period (28 to 52 weeks) | 
| Change from baseline in LCQ | Leicester Cough Questionnaire (LCQ) | over the DB treatment period (28 to 52 weeks) | 
| Change from baseline in QoL-B scales (excluding QoL-B-RSS secondary endpoint) | The Quality of Life-Bronchiectasis (QoL-B) is a 37-item questionnaire with 8 scales (Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions, and Treatment Burden Scales). Each scale is standardized from 0 to 100, with higher scores indicative of better health-related quality of life. | over the DB treatment period (28 to 52 weeks) | 
| Change from baseline in SGRQ | St. George's Respiratory Questionnaire (SGRQ) | over the DB treatment period (28 to 52 weeks) | 
| Safety and tolerability of benralizumab | Will be evaluated in terms of frequency and rate of: Adverse Events (AEs), abnormal vital signs, abnormal results of clinical laboratory assessments, abnormal findings in physical examinations, and abnormal findings in Electrocardiograms (ECGs). Assessments related to AEs cover: Occurrence/Frequency Relationship to IP as assessed by Investigator Intensity Seriousness Death AEs leading to discontinuation of IP Other significant AEs | over the DB treatment period (28 to 52 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Benralizumab, Non-cystic Fibrosis Bronchiectasis, Eosinophlic Inflammation