Study to Evaluate the Efficacy and Safety of MEDI-563 in Adults With Uncontrolled Asthma

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the effect of multiple-dose subcutaneous administrations of MEDI-563 on adults with uncontrolled asthma.

Detailed Description
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This is a Phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of multiple-dose (7 doses) subcutaneous administration of benralizumab (MEDI-563) in adult subjects with uncontrolled asthma.

Official Title
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A Phase 2b, Dose-ranging Study to Evaluate the Efficacy and Safety of MEDI-563 in Adults With Uncontrolled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Biological: Benralizumab 2 mg
* Biological: Benralizumab 20 mg
* Biological: Benralizumab 100 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 through 75 years at the time of screening Adequate contraception from screening through end of trial Weight of more than (>) 45 kilogram (kg) but less than or equal to (<=) 150 kg (>100 pound [lb] but <=330 lb) History of physician-diagnosed asthma for at least 12 months prior to screening Physician prescribed daily use of medium-dose or high-dose inhaled corticosteroid(s) (ICS) plus long-acting beta 2 agonist (LABA) for at least 12 months prior to screening Willingness to switch to an ICS/LABA combination product Dose of other asthma controller medications must be stable for at least 30 days prior to screening At least 2 documented asthma exacerbations in the 12 months prior to screening that required use of a systemic corticosteroid burst For subjects 65 years of age or older, a chest x-ray (CXR) or chest computed tomography (CT) that is normal for an asthmatic population Ability and willingness to complete the study to Week 66, and if needed to Week 92. Exclusion Criteria: Known history of allergy or reaction to any component of the investigational product formulation History of anaphylaxis to any biologic therapy Unexplained diarrhea within 30 days prior to screening or diagnosis of helminth parasitic infestation within 6 months prior to screening Use of immunosuppressive medication within 3 months prior to screening. Chronic oral prednisone or equivalent up to 10 milligram (mg) daily or 20 mg every other day for asthma is allowed Oral corticosteroid burst or short-acting systemic corticosteroid within 30 days prior to screening or during the screening/run-in period Acute upper or lower respiratory infections requiring antibiotics or antiviral medications within 30 days prior to the screening or during the screening/run-in period Receipt of immunoglobulin or blood products within 30 days prior to screening Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to screening, whichever is longer Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to screening, whichever is longer Previously received MEDI-563 Any clinically relevant abnormal findings in physical examination Past history of clinically significant cardiac disease or any electrocardiogram (ECG) abnormality Breastfeeding or lactating women History of alcohol or drug abuse within 12 months prior to screening History of any known primary immunodeficiency disorder Positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol A positive human immunodeficiency virus (HIV) test or subject taking antiretroviral medications History of cigarette smoking more than or equal to (>=) 10 pack-years or smoking within 12 months prior to screening. Known exposure to inhaled occupational agents or fumes with an established diagnosis of occupational asthma History of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy >=12 months prior to screening or other malignancies treated with apparent success with curative therapy >=5 years prior to screening Stable dose of allergy vaccination regimen for less than 30 days prior to screening Subjects unable to demonstrate acceptable inhaler and peak flow meter techniques.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Eosinophilic phenotype (EOS+) Placebo<br>EOS+ (defined as ELEN Index [proprietary mathematical algorithm to predict sputum eosinophil's greater than or equal to 2 percent] positive and/or FeNO [fraction of exhaled nitric oxide] greater than or equal to [>=] 50 parts per billion [ppb]) participants received matching placebo injections subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Other: Placebo<br>* EOS+ and EOS- participants received two placebo injections subcutaneously.<br>|
| Experimental: EOS+ Benralizumab (2 mg)<br>EOS+ participants received single benralizumab 2 milligram (mg) injection subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Biological: Benralizumab 2 mg<br>* EOS+ participants received single benralizumab 2 milligram (mg) injection followed by a single placebo injection subcutaneously.<br>* Other names: MEDI-563;|
| Experimental: EOS+ Benralizumab (20 mg)<br>EOS+ participants received single benralizumab 20 mg injection subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Biological: Benralizumab 20 mg<br>* EOS+ participants received single benralizumab 20 mg injection followed by a single placebo injection subcutaneously.<br>* Other names: MEDI-563;|
| Experimental: EOS+ Benralizumab (100 mg)<br>EOS+ participants received benralizumab 50 mg as two injections subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Biological: Benralizumab 100 mg<br>* EOS+ and EOS- participants received two benralizumab 50 mg injections subcutaneously.<br>* Other names: MEDI-563;|
| Placebo Comparator: Non-eosinophil phenotype (EOS-) Placebo<br>EOS- (defined as ELEN Index negative and FeNO <50 ppb) participants received matching placebo subcutaneous every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Other: Placebo<br>* EOS+ and EOS- participants received two placebo injections subcutaneously.<br>|
| Experimental: EOS- Benralizumab (100 mg)<br>EOS- participants received benralizumab 50 mg as two injections subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40. | Biological: Benralizumab 100 mg<br>* EOS+ and EOS- participants received two benralizumab 50 mg injections subcutaneously.<br>* Other names: MEDI-563;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Asthma Exacerbation Rate (AER) for Eosinophilic Phenotype (EOS+) Participants | The annual asthma exacerbation rate (AER) was calculated as the total number of observed exacerbations in each group up to week 52, divided by total duration of person-year follow-up in each group. An asthma exacerbation is defined as a progressive increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that does not resolve after the initiation of rescue medications and remains troublesome for the participant resulting in either 1) use of systemic corticosteroids or increase of a stable systemic maintenance dose for a duration of at least 3 days as prescribed or administered by the investigator or healthcare provider; or 2) participant initiation of systemic corticosteroids (tablets, suspension or injection) for a duration of at least 3 days as outlined in the Asthma Action Plan provided to the participant by the investigator on Day 1. | Week 1 up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Response in EOS+ Participants |  | Baseline up to Week 66 | 
| Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ss) |  | Pre-dose (0 hour), Post-dose on Day 1, 6, Week 4, 16, 24, 32, 40, and 52 | 
| Dose-Normalized Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ssD) |  | Pre-dose (0 hour), Post-dose on Day 1, 6, Week 4, 16, 24, 32, 40, and 52 | 
| Percentage of Participants With Anti-Drug Antibodies (ADA) to Benralizumab in Eosinophilic Phenotype (EOS+) Participants | Immunogenicity assessment included determination of anti-drug (benralizumab) antibodies in serum samples. ADA positive was defined as a titer >=50 at any point in the study. It was observed at baseline and any visit during the study. | Baseline up to Week 92 | 
| Change From Baseline in Asthma Control Questionnaire (6-items) (ACQ-6) Score at Week 52 | 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 was the mean of the 6 item scores with a score range of 0 (well controlled) to 6 (extremely poor controlled). Data collected on Day 1 prior to dosing was considered as baseline. Results were reported for overall ACQ score. ACQ-6 score was summarized together for all participants. | Baseline up to Week 52 | 
| Change From Baseline in Mean Total Nasal Symptoms Score (TNSS) at Week 52 | Total Nasal Symptoms Score (TNSS) is a 3-item questionnaire, the sum of nasal symptoms, namely, nasal obstruction (rhinorrhea), nasal congestion, and nasal itching/sneezing. Each symptom was rated on a scale from 0-3, with 0 representing no symptoms, 1 mild, 2 moderate, and 3 severe symptoms. TNSS score was a summation of the 3 individual nasal symptom. TNSS score could range from 0 to 9 where higher score indicates worsening. Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline up to Week 52 | 
| Change From Baseline in Mean Asthma Symptom Diary Score at Week 51-52 | Asthma Symptom Diary included 7 questions about the participant symptom and the overall impact of treatment on the disease during the study period. Mean scores of the 7 questions were calculated to identify asthma symptom-free days. Asthma Symptom Diary Scores were analyzed on a bi-weekly basis and compared to baseline scores. Overall symptom score=(daytime frequency score + daytime severity score + nighttime severity score)/3, where total score ranges from 0 to 9. Higher score represents worsening. Mean asthma symptom diary score were summarized together for all participants. Mean asthma symptom diary score were summarized together for all participants. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline up to Week 51-52 | 
| Change From Baseline in Rescue Medication Use at Week 51-52 | Participants were provided inhalers of the same dose (medium- or high-dose) inhaled corticosteroid (ICS) plus long-acting beta antagonist (LABA) combination product as baseline prophylactic medication and continued with same dose throughout the study. Rescue medications such as short-term beta2 agonists were used as first-line treatment for worsening asthma symptoms. Investigator prescribed additional short term asthma controller medications included additional ICS, theophylline, inhaled cromones or antimuscarinics; if asthma symptoms remained mild but not resolved. If asthma symptoms worsened, participants received an oral corticosteroid burst. All rescue medications use with prophylactic medication (+ prophylactic) and without prophylactic medication (- prophylactic) was recorded in asthma symptom dairy by participant. Rescue medication use was analyzed on a bi-weekly basis and compared to baseline scores. | Baseline up to Week 51-52 | 
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 52 | FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline and Week 52 | 
| Change From Baseline in Mean Forced Vital Capacity (FVC) at Week 52 | Forced Vital Capacity (FVC) was the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. | Baseline and Week 52 | 
| Change From Baseline in Peak Expiratory Flow (PEF) at Week 52 | The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed while sitting or standing prior to using any medication (if needed) for asthma. Home PEF was determined separately for morning and evening, and were averaged for each participant. Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline and Week 52 | 
| Change From Baseline in Asthma Quality of Life Questionnaire (Standardized Version) (AQLQ[S]) Score at Week 52 | AQLQ: a 32-item questionnaire evaluating quality of life of participants with asthma 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). The AQLQ(S) responses were categorized as improvement (defined as change from baseline >=0.5), no change (defined as change from baseline >= -0.5 to less than [<] 0.5), and worse (defined as change from baseline < -0.5). Data was summarized by each treatment group. | Baseline and Week 52 | 
| Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D) Health State Evaluation at Week 52 | The utility-based EQ-5D questionnaire comprises of two parts and provides a generic measure of health for clinical and economic appraisal. The health state valuation was the summary score of mobility, self-care, usual activities, pain/discomfort and anxiety/depression on a 3 category scale (no problem, moderate problem, severe problems). Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline and Week 52 | 
| Change From Baseline in EQ-5D Visual Analog Scale (VAS) at Week 52 | The utility-based EQ-5D questionnaire comprises of two parts and provides a generic measure of health for clinical and economic appraisal. The EQ-5D VAS was measured from 0 (worst imaginable health state) to 100 (best imaginable health state). Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline and Week 52 | 
| Change From Baseline in Percentage of Nocturnal Awakening-Free Nights at Week 51-52 | Percentage of nocturnal awakening-free nights were analyzed on a bi-weekly basis and compared to baseline scores. Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline up to Week 51-52 | 
| Change From Baseline in Mean Fraction Exhaled Nitric Oxide (FeNO) at Week 52 | Data was summarized by each treatment group. In addition, data was summarized together for EOS+ and EOS- Placebo arms and EOS+ and EOS- benralizumab 100 mg arms. | Baseline up to Week 52 | 

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