A Study to Evaluate the Effectiveness and Safety of MEDI-528 in Adults

Study Overview
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Brief Summary
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To study the effectiveness and safety of multiple-doses of MEDI-528 on asthma control in adult participants with uncontrolled, moderate-to-severe, persistent asthma.

Detailed Description
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The primary objective of this study is to evaluate the effect of multiple-dose subcutaneous (SC) administration of MEDI-528 on asthma control in adults with uncontrolled, moderate-to-severe, persistent asthma.

Official Title
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A Phase 2b, Randomized Study to Evaluate the Efficacy and Safety of Subcutaneous MEDI-528 in Adults With Uncontrolled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Biological: MEDI528 30 mg
* Biological: MEDI528 100 mg
* Biological: MEDI528 300 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must meet all of the following criteria: Male or female Age 18 through 65 years at the time of screening Written informed consent and any locally required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations Female subjects of childbearing potential who are sexually active with non-sterilized male partner must use adequate contraception from screening through the end of the study. An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception Non-sterilized males who are sexually active with a female of child-bearing potential must use adequate contraception from screening through the end of the study Females or female partners not of childbearing potential must have been surgically sterilized (eg, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as at least 1 year since last regular menses) Sterilized males must be at least 1-year post vasectomy and have obtained documentation of the absence of sperm in the ejaculate Weight ≥ 45 kg but ≤ 120 kg and body mass index (BMI) between 18 and 35 kg/m2 Physician-diagnosed asthma by medical chart Currently taking inhaled corticosteroids (ICS) or is a candidate to receive ICS per Expert Panel Report (EPR)-3 Pre-bronchodilator forced expiratory volume in 1 second (FEV1) value ≥ 40% at Day -28 and Day 1 A post-bronchodilator increase in FEV1 and/or FVC ≥ 12% and ≥ 200 mL at Day -28 OR meeting any one of the following criteria: Proof of post-bronchodilator reversibility of airflow obstruction ≥ 12% documented within 36 months prior to randomization or proof of a positive response to a methacholine challenge documented within 36 months prior to randomization; OR Proof of partial reversibility of ≥ 8% to < 12% improvement in post-bronchodilator FEV1 on Day -28 and achievement of ≥ 12% reversibility at a second time between Day -27 and Day -15; OR If a) and b) are not met and all other inclusion/exclusion criteria are met, subjects with a FEV1 of ≥ 1.5 L and ≥ 60% on Day -14 will be eligible to undergo a methacholine challenge. If the subject achieves a positive response to this methacholine challenge, then this criterion is met Uncontrolled asthma consistent with EPR-3. In the 28 days before screening, subjects should have a history of one or more of the following: Daytime asthma symptoms ≥ 2 days/week Nighttime awakening ≥ 1 night/week Albuterol/salbutamol use ≥ 2 days/week An Asthma Control Questionnaire (ACQ) score ≥ 1.5 at Day -28 and at Day 1. At least one asthma exacerbation in the 12 months before screening that required intake of systemic corticosteroids after an unscheduled medical encounter or as agreed with a physician based on an asthma action plan that defines when oral steroids can be taken by the subject Ability and willingness to complete the follow-up period through Day 323 as required by the protocol. Exclusion Criteria Any of the following would exclude the subject from participation in the study: Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results Concurrent enrollment in another clinical study Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals Known history of allergy or reaction to any component of the investigational product formulation History of anaphylaxis to other biologic therapy Lung disease other than asthma (eg, chronic obstructive pulmonary disease [COPD], cystic fibrosis) Severe depression as measured by a depression score > 15 on the Hospital Anxiety and Depression Scale (HADS) at either Day-28 or Day 1. History of suicidal behavior in the previous 3 years as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) at Day -28. Acute illness other than asthma at the screening and randomization visits History of an active infection within 28 days before and during the screening period, or evidence of clinically significant active infection, including ongoing chronic infection History of ingestion of untreated water in a location known to be infected with parasites, resulting in acute or chronic diarrhea; history of recent travel to areas where parasite infestations are endemic within 6 months before screening; or a diagnosis of parasitic infection within 6 months before screening Use of immunosuppressive medication (except oral prednisone up to a dose of 20 mg every other day or equivalent [eg, 10 mg a day or 5 mg twice a day] and inhaled and topical corticosteroids) within 28 days before randomization Receipt of immunoglobulin or blood products within 28 days before randomization Plans to donate blood during the entire study period Donated blood or has had a blood transfusion within 28 days before screening Receipt of any non-biological study drugs or interventional therapy (including surgical procedures) within 28 days of the first dose of investigational product in this study Receipt of any biologicals including MEDI-528 within 5 half-lives before the first dose of investigational product in this study History of any known immunodeficiency disorder A positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject's verbal report A positive human immunodeficiency virus test or is taking antiretroviral medications, as determined by medical history and/or subject's verbal report A live attenuated vaccination received within 28 days before screening History of clinically significant abnormality on electrocardiogram (ECG) in the opinion of the investigator Breastfeeding or lactating History of treatment for alcohol or drug abuse within the past year History suggestive of COPD or of tobacco smoking ≥ 10 pack-years Evidence of any uncontrolled systemic disease upon physical examination History of cancer, apart from basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy ≥ 1 year before Day 1 or other malignancies treated with apparent success with curative therapy ≥ 5 years before screening Any noninfectious disease involving multiple organs (eg, cystic fibrosis, systemic lupus erythematosus, hemophilia, multiple sclerosis, etc.) that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results Individuals who are legally institutionalized

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: MEDI528 30 mg<br>MEDI-528 at a dose of 30 mg administered as a subcutaneous injection every 2 weeks for 24 weeks | Biological: MEDI528 30 mg<br>* MEDI-528 at a dose of 30 mg administered as a subcutaneous injection every 2 weeks for 24 weeks<br>|
| Experimental: MEDI528 100 mg<br>MEDI-528 at a dose of 100 mg administered as a subcutaneous injection every 2 weeks for 24 weeks | Biological: MEDI528 100 mg<br>* MEDI-528 at a dose of 100 mg administered as a subcutaneous injection every 2 weeks for 24 weeks<br>|
| Experimental: MEDI528 300 mg<br>MEDI-528 at a dose of 300 mg administered as a subcutaneous injection every 2 weeks for 24 weeks | Biological: MEDI528 300 mg<br>* MEDI-528 at a dose of 300 mg administered as a subcutaneous injection every 2 weeks for 24 weeks<br>|
| Experimental: Placebo<br>Placebo administered as a subcutaneous injection every 2 weeks for 24 weeks | Other: Placebo<br>* Placebo administered as a subcutaneous injection every 2 weeks for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change at Day 92 From Baseline in Mean Asthma Control Questionnaire (ACQ) Scores (Intent-toTreat Analysis) | Change at Day 92 from baseline (Day 1, prior to dosing) in mean ACQ scores in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Day 92 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Asthma Exacerbation Rate Through Day 92 (Intent-to-Treat Analysis) | Weighted asthma exacerbation rate (total number of exacerbation rate in each group per total duration of participant-year follow-up in each group) between Day 1 and Day 92 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 92 | 
| Weighted Asthma Exacerbation Rate Through Day 176 (Intent-to-Treat Analysis) | Weighted asthma exacerbation rate (total number of exacerbation rate in each group per total duration of participant-year follow-up in each group) between Day 1 and Day 176 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 176 | 
| Proportion of Participants Experiencing at Least One Asthma Exacerbation Through Day 92 (Intent-to-Treat Analysis) | The proportion of participants that experienced at least one asthma exacerbation between Day 1 and Day 92 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 92 | 
| Proportion of Participants Experiencing at Least One Asthma Exacerbation Through Day 176 (Intent-to-Treat Analysis) | The proportion of participants that experienced at least one asthma exacerbation between Day 1 and Day 176 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 176 | 
| Time to First Asthma Exacerbation Through Day 92 (Intent-to-Treat Analysis) | Time to first asthma exacerbation between Day 1 and Day 92 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 92 | 
| Time to First Asthma Exacerbation Through Day 176 (Intent-to-Treat Analysis) | Time to first asthma exacerbation between Day 1 and Day 176 in pariticpants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). An exacerbation was defined as a progressive increase of asthma symptoms AND a reduction of 20% or more in peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) from baseline (Day 1, prior to dosing) or best previously measured value prior to the current event that did not resolve after the initiation of rescue medications; and results in a prescription for/or administration of systemic corticosteroid burst therapy by the investigator or health care provider. An exacerbation event was considered resolved when the subject's asthma symptoms diminished and PEF or FEV1 return to greater than 80% of baseline for 7 or more days after completion of systemic corticosteroid burst therapy. | Days 1 - 176 | 
| Change at Day 176 From Baseline in Mean Asthma Control Questionnaire Scores (Intent-to-Treat Analysis) | Change at Day 176 from baseline (Day 1, prior to dosing) in mean ACQ scores in participants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Day 176 | 
| Proportion of Participants Achieving Mean Asthma Control Questionnaire (ACQ) Scores at Day 92 of < or = 0.75, > 0.75 to < 1.5, and > or = 1.5 (Intent-to-Treat Analysis) | Proportion of participants achieving mean ACQ scores of < or = 0.75, > 0.75 to < 1.5, and > or = 1.5 at Day 92 in participants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Day 92 | 
| Proportion of Participants Achieving Mean Asthma Control Questionnaire (ACQ) Scores at Day 176 of < or = 0.75, > 0.75 to < 1.5, and > or = 1.5 (Intent-to-Treat Analysis) | Proportion of participants achieving mean ACQ scores of < or = 0.75, > 0.75 to < 1.5, and > or = 1.5 at Day 176 in participants receiving 30, 100, or 300 mg MEDI-528 versus placebo (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Day 176 | 
| Time to First Observed Mean Asthma Control Questionnaire (ACQ) Change From Baseline > or = 0.5 Through Day 92 (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the time to first observed mean ACQ change from baseline (Day 1, prior to dosing) > or = 0.5 through Day 92 (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Days 1 - 92 | 
| Time to First Observed Mean Asthma Control Questionnaire (ACQ) Change From Baseline > or = 0.5 Through Day 176 (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the time to first observed mean ACQ change from baseline (Day 1, prior to dosing) > or = 1.5 Through Day 176 (Intent-to-Treat Analysis). The 6-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants were asked to recall how their asthma had been during the previous week. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score ≥ 1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful. | Days 1 - 176 | 
| Change at Day 92 From Baseline in Forced Expiratory Volume in One Second (FEV1) (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the mean change at Day 92 from baseline (Day 1, prior to dosing) in FEV1. | Day 92 | 
| Change at Day 176 From Baseline in Forced Expiratory Volume in One Second (FEV1) (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the mean change from baseline (Day 1, prior to dosing) in FEV1 at Day 176 | Day 176 | 
| Proportion of Participants Who Had a Asthma Quality of Life Questionnaire - Standard (AQLQ[S]) Assessment Response at Day 85 (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the proportion of participants who had an AQLQ(S) assessment response (defined as an improvement of at least 0.5 score in AQLQ[S]) at Day 85 (Intent-to-Treat Analysis). The AQLQ(S) is a 32-item questionnaire that measures the health related quality of life experienced by asthma patients. In the study, 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 is calculated as the mean response to all questions. Individual improvement in the overall score of 0.5 has been identified as the minimally important difference, with score changes > 1.5 identified to be large meaningful differences. | Day 85 | 
| Proportion of Participants Who Had a Asthma Quality of Life Questionnaire - Standard (AQLQ[S]) Assessment Response at Day 176 (Intent-to-Treat Analysis) | Effect of MEDI-528 (30, 100, or 300 mg) versus placebo on the proportion of participants who had an AQLQ(S) assessment response at Day 176 (Intent-to-Treat Analysis). The AQLQ(S) is a 32-item questionnaire that measures the health related quality of life experienced by asthma patients. In the study, 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 is calculated as the mean response to all questions. Individual improvement in the overall score of 0.5 has been identified as the minimally important difference, with score changes > 1.5 identified to be large meaningful differences. | Day 176 | 
| Proportion of Participants With Detectable Anti-drug Antibodies to MEDI-528 | Proportion of participants with detectable anti-drug antibodies to MEDI-528 in subjects receiving 30, 100, or 300 mg MEDI-528 and placebo | Days 1, 29, 57, 85, 127, 169, 176, 204,260, and 323 | 
| First Dose Trough Concentration of MEDI-528 | First dose trough concentration of MEDI-528 measured on Day 15 prior to administration of the second dose of MEDI-528 (30, 100, or 300 mg). Serum concentrations of MEDI-528 were measured on Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323. The first dose trough concentration of MEDI-528 was measured on Day 15 prior to the Day 15 dose. | Day 15 | 
| Day 169 Steady State Trough Concentration of MEDI-528 | Trough concentration of MEDI-528 measured on Day 169 prior to administration of the last dose of MEDI-528 (30, 100, or 300 mg). Serum concentrations of MEDI-528 were measured on Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323. Steady state trough concentration of MEDI-528 was measured on Day 169. | Day 169 | 
| Half Life of MEDI-528 | Half life of MEDI-528 in subjects receiving 30, 100, or 300 mg MEDI-528. Serum concentrations of MEDI-528 were measured on Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323. | Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323 | 
| Accumulation Ratio of Trough Concentrations of MEDI-528 | Accumulation ratio of trough concentrations of MEDI-528 in subjects receiving 30, 100, or 300 mg MEDI-528. Serum concentrations of MEDI-528 were measured on Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323. | Days 1, 15, 29, 57, 85, 127, 169, 176, 204, 232, 260, 288, and 323 |