Study of Efficacy and Safety of Brodalumab Compared With Placebo in Adults With Inadequately Controlled Asthma With High Bronchodilator Reversibility

Study Overview
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Brief Summary
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The purpose of this study is to determine if brodalumab (AMG 827) is safe and effective compared to placebo as measured by change in Asthma Control Questionnaire (ACQ) composite scores.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Brodalumab in Subjects With Inadequately Controlled Asthma and High Bronchodilator Reversibility

Conditions
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Asthma

Intervention / Treatment
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* Biological: Placebo
* Biological: Brodalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of asthma, and presently has reversibility over pre-bronchodilator forced expiratory volume in 1 second (FEV1) of ≥ 20% at screening Percent of predicted FEV1 ≥ 40% and ≤ 80% at screening Inhaled corticosteroid (ICS) ≥ 200 and ≤ 1000/μg/day fluticasone powder or equivalent Ongoing asthma symptoms with asthma control questionnaire (ACQ) composite score at screening and baseline ≥ 1.5 points Exclusion Criteria: History of chronic obstructive pulmonary disease (COPD) or other chronic pulmonary condition other than asthma History of allergic bronchopulmonary aspergillosis Respiratory infection within 4 weeks of screening or 1 week of baseline visit Subject has known history of Crohn's disease Subject has any other significant concurrent medical condition of laboratory abnormalities, as defined in the study protocol Subject has previously used any anti-interleukin-17 (IL17) biologic therapy Subject is pregnant or breastfeeding, or planning to become pregnant while enrolled in the study Female subject is unwilling to use highly effective methods of birth control unless 2 years post-menopausal or surgically sterile Subject has severe depression measured by Personal Health Questionnaire Depression Scale (PHQ-8) or suicidal ideation/behavior as measured by and Columbia Suicide Severity Rating Scale (e-CSSRS) Subject has a history or evidence of psychiatric disorder or substance abuse considered by the Investigator to pose a risk to subject safety

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo administered by subcutaneous injection on day 1, week 1, week 2 and every 2 weeks thereafter for 24 weeks. | Biological: Placebo<br>* Placebo administered subcutaneously<br>|
| Experimental: Brodalumab 210 mg<br>Participants received 210 mg brodalumab administered by subcutaneous injection on day 1, week 1, week 2, and every 2 weeks thereafter for 24 weeks. | Biological: Brodalumab<br>* Brodalumab administered subcutaneously<br>* Other names: AMG 827;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Asthma Control Questionnaire (ACQ) Composite Score at Week 24 | The ACQ is a validated instrument used in clinical research and practice to evaluate asthma control/impairment. The ACQ assesses disease control by evaluating 7 questions: night time awakenings, asthma symptoms upon wakening, activity limitation, shortness of breath, wheeze frequency, short-acting bronchodilator use, and FEV1. All seven items are scored on a 7-point scale, with 0 indicating good control and 6 indicating poor control; the total score is the mean of the seven items and ranges from 0 (totally-controlled) to 6 (extremely poorly controlled). A negative change from baseline indicates improvement. A change of 0.50 points is considered clinically meaningful and a total score of < 1.0 indicates good asthma control. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Exacerbation Rate | The asthma exacerbation event rate is defined as the number of events per subject-year during the 24 week treatment period. An asthma exacerbation was defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study; distinct asthma exacerbations were defined as events with start dates more than 10 days apart from each other. | Baseline to week 24 | 
| Change From Baseline in ACQ Composite Score at Week 24 in ICS+LABA Subpopulation | The ACQ is a validated instrument used in clinical research and practice to evaluate asthma control/impairment. The ACQ assesses disease control by evaluating 7 questions: night time awakenings, asthma symptoms upon wakening, activity limitation, shortness of breath, wheeze frequency, short-acting bronchodilator use, and FEV1. All seven items are scored on a 7-point scale, with 0 indicating good control and 6 indicating poor control; the total score is the mean of the seven items and ranges from 0 (totally-controlled) to 6 (extremely poorly controlled). A negative change from baseline indicates improvement. A change of 0.50 points is considered clinically meaningful and a total score of < 1.0 indicates good asthma control. | Baseline and week 24 | 
| Asthma Exacerbation Rate in ICS+LABA Subpopulation | The asthma exacerbation event rate is defined as the number of events per subject-year during the 24 week treatment period. An asthma exacerbation was defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study; distinct asthma exacerbations were defined as events with start dates more than 10 days apart from each other. | Baseline to week 24 | 
| Change From Baseline in Daily Asthma Symptom Score (7-day Average Score) | The Asthma Symptom Diary (ASD) consists of 23 questions answered on a handheld device, including 10 asthma symptom-related items (5 answered in the morning and 5 in the evening). The morning diary comprises questions on 4 asthma-related symptoms (wheezing, shortness of breath, cough, chest tightness), rated on a 5-point severity scale from 0 (no symptom) to 4 (very severe symptoms), and 1 question on nocturnal awakenings, rated from 0 (did not wake up) to 4 (unable to sleep due to asthma). The evening diary has questions on the same 4 asthma-related symptoms and 1 question on limitations of activities, rated from 0 (not at all) to 4 (extremely). The ASD daily score is computed by averaging the responses to the 10 symptom-related items, and the mean 7-day ASD score is calculated by averaging the 7 daily scores, with the final score ranging from 0 (minimal symptoms) to 4 (very severe symptoms). | Baseline and week 24 | 
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) |  | Baseline and week 24 | 
| Change From Baseline in Daily Rescue Short-acting Beta-agonist Use | Participants were permitted allowed to use their inhaled rescue medication (SABA) as needed throughout the study and the use was captured in the daily electronic diary (eDiary). | Baseline and week 24 | 
| Time to First Asthma Exacerbation | An asthma exacerbation is defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study. Median time to first asthma exacerbation could not be estimated, the percentage of participants with an asthma exacerbation is reported. | From first dose of study drug to week 24 | 
| Number of Participants Who Experienced an Asthma Exacerbation | An asthma exacerbation is defined as an asthma worsening that requires systemic corticosteroids for at least 3 days during the study. | Baseline to week 24 | 
| Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Overall Score | The AQLQ is an asthma-specific instrument that includes evaluations of both symptoms and health-related quality of life measures. The 32-item instrument measures 4 domains affected by asthma including activity limitations, emotional function, exposure to environmental stimuli, and symptoms. Participants were asked to recall their experiences during the last 2 weeks and to respond to each question on a 7-point scale (7=no impairment, 1=severe impairment). The overall score was calculated as mean of the responses to the 32 questions and ranges from 1 (severe impairment) to 7 (no impairment). A positive change from baseline indicates improvement. | Baseline and week 24 | 
| Change From Baseline in Morning and Evening Peak Expiratory Flow Rate (PEFR) | Peak expiratory flow rate was measured by the participant twice daily at approximately the same time each day (eg, within 1 hour of waking and immediately before bedtime) using a peak flow meter. | Baseline and week 24 | 
| Change From Baseline in Variation of Peak Flow | Peak flow was measured by the participant twice daily at approximately the same time each day (eg, within 1 hour of waking and immediately before bedtime) using a peak flow meter. The variation of peak flow is defined as the absolute value of the difference between the A.M. and P.M. peak flow in one day for an individual participant. | Baseline and week 24 | 
| Proportion of Asthma Symptom-free Days in 4-weeks Intervals Over the Treatment Period | Asthma symptom-free days is defined as days that a participant had a score of zero in their daily asthma symptom diary score. The ASD consists of 23 questions answered on a handheld device, including 10 asthma symptom-related items (5 answered in the morning and 5 in the evening). The morning diary comprises questions on 4 asthma-related symptoms (wheezing, shortness of breath, cough, chest tightness), rated on a 5-point severity scale from 0 (no symptom) to 4 (very severe symptoms), and 1 question on nocturnal awakenings, rated from 0 (did not wake up) to 4 (unable to sleep due to asthma). The evening diary has questions on the same 4 asthma-related symptoms and 1 question on limitations of activities, rated from 0 (not at all) to 4 (extremely). The daily score is the average of the responses to the 10 items. | Baseline (the 4 weeks prior to first dose) and 4-week intervals up to week 24 | 
| Serum Brodalumab Concentration | Serum brodalumab concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) = 0.0500 µg/mL; values below the LLOQ were set to zero. | Day 1 and weeks 1, 2, 4, 8, 12, 16, and 22 at predose, week 2 + 3 days, week 22 + 3, 7, 10, and 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inadequately controlled asthma, brodalumab, AMG 827