A Phase 2 Study to Evaluate the Safety and Efficacy of Intravenously Administered Benralizumab (MEDI-563).

Study Overview
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Brief Summary
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The study will evaluate the effect of two intravenous dose regimens of benralizumab (MEDI-563) on the proportion of adult subjects with asthma exacerbations who required an urgent healthcare visit for treatment of an acute asthma exacerbation.

Detailed Description
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The study will evaluate the effect of two intravenous dose regimens of benralizumab (MEDI-563) (0.3 milligram per kilogram [mg/kg] of body weight and 1.0 mg/kg of body weight) on the proportion of adult subjects with asthma exacerbations (relapse and de novo) who required an urgent healthcare visit for treatment of an acute asthma exacerbation.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Intravenously Administered MEDI-563, A Humanized Anti-interleukin-5 Receptor Alpha Monoclonal Antibody, on Asthma Control Following Acute Exacerbations in Adults

Conditions
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Asthma

Intervention / Treatment
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* Other: Placebo
* Biological: Benralizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18 to 60 years at the time of the administration of investigational product Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization (applies to covered entities in the US only) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations Physician-diagnosed asthma with a duration of greater than or equal to (>=) 2 years by medical chart or subject report Had an asthma exacerbation requiring urgent care in the year prior to screening Meets National Heart, Lung, and Blood Institute (NHLBI) for persistent asthma in the 3 months prior to the current urgent healthcare visit Current asthma exacerbation that must have lasted >= 2 hours prior to arrival to the urgent healthcare setting Requires at least 2 treatments of inhaled bronchodilators for the current asthma exacerbation in the urgent healthcare setting or within the emergency medical system (EMS) for >= 1 hour Shows an FEV1 or PEF of not more than 70 percent (%) predicted after 1 hour of treatment of the current asthma exacerbation Women of child-bearing potential, unless surgically sterile (including tubal ligation) and/or at least 2 years post-menopausal, must have used 2 effective methods of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap, abstinence, use of a condom with spermicide by the sexual partner, or sterile sexual partner) from screening through the end of the study (Day 84; Cessation of birth control after this point should be discussed with a responsible physician) Men, unless surgically sterile, must likewise practice 2 effective methods of birth control (condom with spermicide or abstinence) and must use such precautions from Day 0 through Day 84 Otherwise healthy by medical history and physical examination A chest x-ray that is normal for an asthmatic population and excludes alternative diagnosis per the investigation Ability to complete the follow-up period until Day 168 as required by protocol The investigator has determined that the subject is clinically stable and the FEV1, is >= 30% predicted prior to receiving investigational product on Day 0. Exclusion Criteria: Known history of allergy or reaction to any component of the investigational product formulation Acute illness other than asthma at the start of the study Fever more than (>) 38.6 degrees Celsius (C) (>101.5 degrees Fahrenheit [F]) Current acute asthma attack is due to aspirin-induced asthma Current asthma episode is an anaphylactoid/anaphylactic reaction presenting with acute bronchospasm Evidence of clinically significant non-respiratory active infection, including ongoing chronic infection History or current prolonged diarrhea, abdominal pain, and/or blood and mucus in stools or have minor symptoms and have exposure to stream or lake water, been exposed to someone who has a parasitic infection (like a family member), or study subject has traveled outside the United States of America (USA) and/or Canada within the last year Use of immunosuppressive medication (except oral prednisone and inhaled and topical corticosteroids) within 30 days before randomization into the study Have received Xolair within 6 months before randomization into the study Receipt of immunoglobulin or blood products within 30 days before randomization into the study Receipt of any investigational drug therapy within 6 months before the first dose of investigational product in this study through Day 168 History of primary immunodeficiency Previous medical history, or evidence, of an intercurrent illness that may compromise the safety of the subject in the study History of clinically significant abnormality on ECG in the opinion of the investigator Pregnancy (must have a negative serum pregnancy test prior to the first dose of investigational product) Breastfeeding or lactating woman History of treatment for alcohol or drug abuse within the past year Diagnosis of chronic obstructive pulmonary disease (COPD) by a healthcare professional Evidence of any clinically significant systemic disease on physical examination History of cancer except basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy >1 year prior to entry or other malignancies treated with apparent success with curative therapy >5 years prior to entry Known exposure to inhaled occupational agents or fumes with an established diagnosis of occupational asthma Any condition (that is, impending ventilatory failure or hemodynamic compromise) that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of study results Any employee of the clinical study site who is involved with the conduct of the study History of cigarette smoking >20 pack years Previously received benralizumab (MEDI-563) Asthma exacerbation due to acute inhalational exposure.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>A single dose of placebo matched to benralizumab (MEDI-563) intravenous infusion over at least 30 minutes on Day 0. | Other: Placebo<br>* A single dose of placebo matched to benralizumab (MEDI-563) intravenous infusion over at least 30 minutes on Day 0.<br>|
| Experimental: Benralizumab 0.3 mg/kg<br>A single dose of benralizumab (MEDI-563) 0.3 milligram per kilogram (mg/kg) of body weight intravenous infusion over at least 30 minutes on Day 0. | Biological: Benralizumab<br>* A single dose of benralizumab (MEDI-563) 0.3 or 1 mg/kg of body weight intravenous infusion over at least 30 minutes on Day 0.<br>* Other names: MEDI-563;|
| Experimental: Benralizumab 1.0 mg/kg<br>A single dose of benralizumab (MEDI-563) 1.0 mg/kg of body weight intravenous infusion over at least 30 minutes on Day 0. | Biological: Benralizumab<br>* A single dose of benralizumab (MEDI-563) 0.3 or 1 mg/kg of body weight intravenous infusion over at least 30 minutes on Day 0.<br>* Other names: MEDI-563;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Asthma Exacerbations at Week 12 | Percentage of participants who required urgent healthcare visit for treatment of acute asthma exacerbation were reported. As per protocol, asthma exacerbation (relapse/de novo) was defined as either 1) increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that did not resolve within 2 hours after use of rescue albuterol or corticosteroids and required an unscheduled medical visit or 2) during scheduled study visit, participant had acute worsening of asthma symptoms and a reduction of greater than or equal to (>=) 20 percent (%) in Peak Expiratory Flow (PEF) or Forced Expiratory Volume in 1 Second (FEV1), which in the opinion of the investigator required treatment with systemic corticosteroids. Asthma exacerbations were analyzed in a non-adjudicated manner (by investigator), which were then adjudicated in a blinded fashion by the sponsor medical monitor prior to database lock to determine whether the reported exacerbation met the protocol definition. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between administration of study drug and Day 84 that were absent before treatment or that worsened relative to pretreatment state. | Day 0 to Day 84 | 
| Percentage of Participants With Asthma Exacerbations at Week 4 and Week 24 | Percentage of participants who required an urgent healthcare visit for treatment of an acute asthma exacerbation were reported. As per protocol, asthma exacerbation (relapse or de novo) was defined as either 1) an increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that did not resolve within 2 hours after the use of rescue albuterol or corticosteroids and required an unscheduled medical visit or 2) during a scheduled study visit, the participant had acute worsening of asthma symptoms and a reduction of >=20% in PEF or FEV1, which in the opinion of the investigator required treatment with systemic corticosteroids. Asthma exacerbations were analyzed in a non-adjudicated manner (by investigator), which were then adjudicated in a blinded fashion by the sponsor medical monitor prior to database lock to determine whether the reported exacerbation met the protocol definition. | Weeks 4 and 24 | 
| Asthma Control Questionnaire (ACQ) Scores | Asthma Control Questionnaire (ACQ) is a participant-reported questionnaire to assess the asthma control with 6 items assessing night-time waking, symptoms on waking, activity limitation, shortness of breath, wheeze, and rescue short-acting beta agonist use. Each item was rated on a 7-point Likert scale ranging from 0 (no impairment) to 6 (maximum impairment). Overall ACQ score is the mean of the 6 item scores with a score range of 0 (well controlled) to 6 (extremely poor controlled). Results were reported for overall ACQ score and 6 item scores. | Days 0, 7, 42, and 84 | 
| Forced Expiratory Volume in 1 Second (FEV1) Recorded at Study Sites | The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Spirometry was performed with the participant in the sitting position at study sites by the investigator or qualified designee according to American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. Multiple forced expiratory efforts (at least 2 but no more than 5) were performed for each office spirometry session and the 2 best efforts that met ATS/ERS acceptability and reproducibility criteria were recorded. The best efforts were based on the highest FEV1. The maximum FEV1 of the 2 best efforts was used for the analysis. | Days 0, 7, 42, and 84 | 
| Forced Expiratory Volume in 1 Second (FEV1) Recorded at Home | The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Home peak flow testing for FEV1 was performed every morning while sitting or standing prior to using any medication (if needed) for asthma. Mean FEV1 values for each week were reported starting from Day 1 to Day 84. | Day 1 to Day 84 | 
| Peak Expiratory Flow (PEF) Recorded at Home | The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Home peak flow testing for PEF was performed every morning while sitting or standing prior to using any medication (if needed) for asthma. Mean PEF values for each week were reported starting from Day 1 to Day 84. | Day 1 to Day 84 | 
| Number of Puffs of Rescue Beta-2 Agonist Per Week | Rescue beta-2 agonist use (total number of puffs for the prior day) was collected daily in the morning by the participants in the electronic daily diary provided to them. Participants were instructed not to collect rescue beta-2 agonist used prior to exercise. Average values for each week were reported starting from Day 1 to Day 84. | Day 1 to Day 84 | 
| Number of Participants With Physician Global Assessment (PGA) at Day 42 and Day 84 | Physician Global Assessment (PGA) consisted of a single physician-rated question assessing participant's status as 'excellent', 'good', 'moderate', 'poor', 'worsening' or 'not applicable (NA)'. Number of participants were categorically summarized. | Days 42 and 84 | 
| Asthma Quality of Life Questionnaire (Standardized Version) (AQLQ[S]) Scores | Asthma Quality of Life Questionnaire (Standardized Version) (AQLQ[S]): a 32-item questionnaire that measures the functional impairments experienced by adult participants including 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli). Participants were asked to recall their experiences during the previous 2 weeks and to score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The overall score was calculated as the mean response to all questions. The 4 domain scores were the means of the responses to the questions in each of the domains. Overall AQLQ score and 4 domain scores ranged from 7 (no impairment) to 1 (severe impairment). | Days 0, 42, and 84 | 
| Number of Healthcare Resources Utilized by Resource Type | Healthcare resource use was summarized by resource type from information on asthma exacerbations, and asthma related medications. Healthcare resource utilization assessed the total number of hospitalizations, urgent care, primary care clinic visits, asthma specialist clinic visits, telephone calls, and home management. | Day 0 to Day 168 | 
| Maximum Observed Serum Concentration (Cmax) for Benralizumab | The Cmax of benralizumab is reported. Non-compartmental pharmacokinetic (PK) analysis was used for evaluation. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Area Under the Serum Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) for Benralizumab | AUClast = area under the concentration-time curve from time 0 to last measurable concentration. Non-compartmental PK analysis was used for evaluation. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Area Under the Serum Concentration-Time Curve From Time 0 to Extrapolated Infinite Time (AUC [0 - Infinity]) for Benralizumab | AUC [0 - infinity] = Area under the serum concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - infinity). It is obtained from AUC (0 - t) plus AUC (t - infinity). Non-compartmental PK analysis was used for evaluation. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Systemic Clearance (CL) for Benralizumab | Systemic clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Non-compartmental PK analysis was used for evaluation. Clearance was normalized to participant's body weight. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Terminal Phase Elimination Half-Life (t1/2) for Benralizumab | Terminal phase elimination half-life is the time measured for the serum concentration to decrease by one half. Non-compartmental PK analysis was used for evaluation. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Volume of Distribution of the Central Compartment (Vc) for Benralizumab | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Vc = volume of distribution of the central compartment, calculated as Dose/Cmax; where Cmax = maximum observed serum concentration. Non-compartmental PK analysis was used for evaluation. Results were normalized to participant's body weight. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Volume of Distribution at Steady State (Vss) for Benralizumab | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Vss = steady state volume of distribution, calculated as MRT*CL, where MRT is the Mean Residence Time and CL is systemic clearance; which is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Non-compartmental PK analysis was used for evaluation. Results were normalized to participant's body weight. | Predose and 1 hour post-end of infusion on Day 0; Days 7, 42, and 84 | 
| Number of Participants With Anti-Drug Antibodies to Benralizumab | Number of participants with anti-drug antibodies to benralizumab is reported. | Day 0 and 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Benralizumab, MEDI-563, Asthma