A Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3b Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients With Severe Asthma Uncontrolled on Standard of Care Treatment
Overview
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- AstraZeneca
- Enrollment
- 660
- Locations
- 1
- Primary Endpoint
- Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)
Overview
Brief Summary
The purpose of this study is to investigate the effect of benralizumab on the rate of asthma exacerbations, patient reported quality of life and lung function during the 24-week treatment in patients with uncontrolled, severe asthma with an eosinophilic phenotype. A subset of patients will be assessed for their ongoing chronic rhinosinusitis with nasal polyps. The study design has been updated to include a 56-week open label ANDHI in Practice (ANDHI IP) sub study upon the completion of the 24-week double-blind period of the ANDHI study.
Detailed Description
This is a Phase IIIb, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and the safety of repeat dosing of benralizumab 30 mg subcutaneous (sc) versus placebo on top of standard of care asthma therapy in patients with severe uncontrolled asthma. Approximately 630 patients with peripheral blood eosinophil counts ≥150 cells/μL will be randomized 2:1 to receive benralizumab 30 mg sc or matched placebo for 24 weeks.
After enrolment, eligible patients will enter an up to 42-day screening/run-in period. Patients who meet eligibility criteria will be randomized 2:1 on Day 0 to receive either benralizumab or placebo every 56 days (every 8 weeks) through Week 16, with end of treatment (EOT) at Day 168 (Week 24). At the completion of the 24-week doubleblind period of the ANDHI study, eligible patients in benralizumab and placebo arm may enter a 56-week open label period (ANDHI in Practice [ANDHI IP] substudy), in which concomitant asthma therapies will be tapered as directed by the protocol in those patients who achieve and maintain asthma control (defined as ACQ6 score <1.5 and no clinically significant asthma exacerbations that required a burst of systemic corticosteroid or a hospitalization due to asthma between reduction visits) with add-on benralizumab.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a history of physician-diagnosed asthma requiring treatment with medium-to-high dose Inhaled Corticosteroids (ICS) plus asthma controller, for at least 12 months prior to Visit
- •Documented current treatment with high daily doses of ICS plus at least one other asthma controller for at least 3 months prior to Visit
- •History of at least 2 asthma exacerbations while on ICS plus another asthma controller that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit
- •ACQ6 score ≥1.5 at Visit
- •Screening pre-bronchodilator (pre-BD) FEV1 of \<80% predicted at Visit
- •Excessive variability in lung function by satisfying ≥ 1 of the following criteria:
- •Airway reversibility (FEV1 ≥12%) using a short-acting bronchodilator demonstrated at Visit 2 or Visit
- •Airway reversibility to short-acting bronchodilator (FEV1 ≥12%) documented during the 12 months prior to enrolment Visit
- •Daily diurnal peak flow variability of \>10% when averaged over 7 continuous days during the study run-in period
- •An increase in FEV1 of ≥12% and 200 mL after a therapeutic trial of systemic corticosteroid (eg, OCS), given outside of an asthma exacerbation, documented in the 12 months prior enrolment Visit
Exclusion Criteria
- •Clinically important pulmonary disease other than asthma
- •Acute upper or lower respiratory infections within 30 days prior to the date informed consent.
- •A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to, standard of care therapy.
- •History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
- •A history of known immunodeficiency disorder.
- •Current smokers or former smokers with a smoking history of ≥10 pack years.
- •Previously received benralizumab (MEDI-563).
- •Receipt of any investigational medication as part of a research study within approximately 5 half-lives prior to randomization.
- •Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
- •Receipt of live attenuated vaccines 30 days prior to the date of randomization; other types of vaccines are allowed.
Arms & Interventions
Benralizumab (Medi-563)
Benralizumab (Medi563) Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).
Intervention: Benralizumab (Medi-563) (Drug)
Placebo
Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)
Time Frame: Baseline (Week 0) up to Week 24
An asthma exacerbation was defined as a worsening of asthma that led to any of the following: * Use of systemic corticosteroids (or temporary increase in stable oral corticosteroids \[OCS\] background dose) for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. * An emergency room/urgent care visit (defined as evaluation and treatment for \< 24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above). * An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. Annual exacerbation rate = 365.25\*total number of exacerbations / total duration of follow-up within the treatment group. Annual asthma exacerbation rates over the 24-week period were estimated using a negative binomial model.
Secondary Outcomes
- Change From Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Change From Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24)(Run-in baseline (from Day -28 to Day 0) and Week 24)
- Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Change From Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Time to First Asthma Exacerbation (up to Week 24)(Baseline (Week 0) up to Week 24)
- Change From Baseline in Short Form 36-item Health Survey, Version 2 (SF-36v2) to the EOT (Week 24)(Baseline (Week 0) and Week 24)
- Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24)(Baseline (Week 0) and Week 24)