Efficacy and Safety Study of Benralizumab to Reduce OCS Use in Patients With Uncontrolled Asthma on High Dose Inhaled Corticosteroid Plus LABA and Chronic OCS Therapy

Phase 3CompletedNCT02075255

AstraZeneca220 enrolled

Overview

The purpose of this trial is to confirm if benralizumab can reduce the use of maintenance OCS in systemic corticosteroid dependent patients with severe refractory asthma with elevated eosinophils.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

220

Conditions

Asthma

Interventions

BenralizumabBIOLOGICAL

Benralizumab administered subcutaneously every 4 weeks

PlaceboBIOLOGICAL

Placebo subcutaneously on study week 0 until study week 24 inclusive.

BenralizumabBIOLOGICAL

Benralizumab administered subcutaneously every 4 weeks for the first 3 dose and then every 8 weeks; matching placebo subcutaneously at the 4 week interim to maintain the blind.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures. 2. Female and male aged from 18 to 75 years, inclusively. 3. History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA. 4. Elevated level of peripheral blood eosinophil 5. Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1 6. Chronic oral corticosteroid therapy for at least 6 continuous months directly preceding Visit 1. Subjects must be on doses equivalent to 7.5 - 40 mg/day of prednisolone/prednisone at Visit 1 and be on a stable dose for at least 2 weeks prior to randomization. Patients must agree to switch to study required prednisone/prednisolone as their oral corticosteroid for the duration of the study. 7. Patients with documented failures of OCS reduction within 6 months prior to Visit 1 will not be required to proceed through the dose optimization phase during run-in. 8. Morning pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted 9. Evidence of asthma as documented by either: Airway reversibility (FEV1 ≥12% and 200 mL) demonstrated at Visit 1, Visit 2, or Visit 3 using the Maximum Post-bronchodilator Procedure OR Documented reversibility in the previous 24 months prior to Visit 1 OR Airway hyperresponsiveness (PC20 FEV1 methacholine concentration ≤8mg/mL) documented in the previous 12 months prior to planned date of randomization OR Airflow variability in clinic FEV1 ≥20% between 2 consecutive clinic visits documented in the 12 months prior to the planned date of randomization (FEV1 recorded during an exacerbation should not be considered for this criterion). All patients must have reversibility testing performed before randomization to establish a baseline characteristic. If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomization, the site should reiterate the need to withhold short- and long-acting bronchodilators prior to Visit 3 in an effort to meet this inclusion criterion. 10. At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained 11. Optimized OCS dose reached at least 2 weeks prior to randomization 12. Additional asthma controller medication must not have been initiated during run in/optimization period (not applicable for management of exacerbations during screening/ run in optimization phase) 13. At least 70% compliance with OCS use 14. At least 70% compliance with usual asthma controller ICS-LABA 15. Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary) Exclusion criteria: 1. Clinically important pulmonary disease other than asthma or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts. 2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 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 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. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during run-in/optimization 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 5. History of life-threatening asthma 6. Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase 7. Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5 8. Receipt of oral corticosteroids, other than prednisone or prednisolone, as the maintenance oral steroid controller for asthma symptoms from Visit 1 and throughout the study. 9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period

Locations (87)

Outcomes

Primary Outcomes

Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control

Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

Time frame: Week 28

Secondary Outcomes

Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control

Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose.

Time frame: Week 28

Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL

Time frame: Week 28

The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control

Data from ClinicalTrials.gov

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Research Site

Los Angeles, California, United States

Research Site

Centennial, Colorado, United States

Research Site

Denver, Colorado, United States

Research Site

Hialeah, Florida, United States

Research Site

Hialeah, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Orlando, Florida, United States

Research Site

Iowa City, Iowa, United States

Research Site

Fort Mitchell, Kentucky, United States

Research Site

Rochester, Minnesota, United States

...and 77 more locations

The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control

Time frame: Week 28

The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control.

Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

Time frame: Week 28

The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control

Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

Time frame: Week 28

Number and Percentage of Patients With ≥1 Asthma Exacerbation

Number and percentage of patients with at least one post randomisation asthma exacerbation.

Time frame: Immediately following the randomisation through Study Week 28

Time to the First Asthma Exacerbation

Time to the first occurrence of asthma exacerbation post randomisation

Time frame: The time from randomisation to the date of first asthma exacerbation over 28 weeks

Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit

Time to the first exacerbation requiring hospitalization or ER visit post randomisation

Time frame: The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.

The Annualized Rate of Asthma Exacerbation

The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up.

Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up

The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization

The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator that are associated with an emergency room visit or a hospitalization adjusted by the time of follow-up.

Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up

Number of Days in Hospital Due to Asthma

Number of days in hospital due to asthma, if none, 0 day is considered

Time frame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up

Change From Baseline to Week 28 in Pre-bronchodilator FEV1

Baseline is defined as the last non-missing value prior to the first dose of study treatment. Change from baseline to Week 28 in two treatment groups is compared to placebo group.