Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma

Study Overview
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Brief Summary
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The purpose of this study is to show whether mepolizumab given every 4 weeks intravenously (i.v.) can reduce the frequency of asthma exacerbations in subjects with severe asthma despite receiving high doses of standard asthma medications. The study will look at different doses of mepolizumab in comparison to a placebo.

Detailed Description
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A double-blind, placebo-controlled study to evaluate the efficacy, safety and pharmacodynamics of three doses (75 mg, 250 mg and 750 mg) of mepolizumab intravenous (i.v.) administered every 4 weeks compared with placebo over a 52-week treatment period in subjects with severe uncontrolled refractory asthma. Efficacy will be measured by the frequency of asthma exacerbations. In addition lung function, rescue medication usage, daily symptoms, asthma control score, asthma quality of life score and withdrawals due to asthma exacerbations will be assessed. Safety will be assessed by adverse events, clinical laboratory evaluations, ECGs, immunogenicity and vital signs. Pharmacodynamics will be assessed by eosinophil levels in blood, serum IL-5 and eosinophil levels in induced sputum.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose Ranging Study to Determine the Effect of Mepolizumab on Exacerbation Rates in Subjects With Severe Uncontrolled Refractory Asthma

Conditions
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Asthma

Intervention / Treatment
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* Biological: Mepolizumab 750
* Biological: Mepolizumab 250
* Biological: Mepolizumab 75
* Drug: Placebo saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Aged 12 to 65 years inclusive Minimum weight 45kg Clinical features of severe refractory asthma Well documented requirement for high dose inhaled corticosteroids (ICS) [i.e. >= 880mcg/day fluticasone propionate or equivalent daily] for at least 12 months Using additional controller medication in addition to high dose ICS for at least 12 months Persistent airflow obstruction indicated by a pre-bronchodilator FEV1<80% predicted at visit 1 or 2 or peak flow diurnal variability of >20% on 3 or more days during the run-in Airway inflammation which is likely to be eosinophilic in nature demonstrated by either raised peripheral blood eosinophils (>=300/microL), sputum eosinophils (>=3%), exhaled nitric oxide (>=50ppb) or prompt deterioration of asthma control following a <=25% reduction in regular maintenance dose of inhaled or oral corticosteroids (OCS) History of 2 or more exacerbations requiring systemic corticosteroids in the previous 12 months Evidence of asthma documented by airway reversibility, airway hyperresponsiveness or airflow variability ECG assessment demonstrating QTc<450msec or QTc<480msec for patients with bundle branch block Liver function tests demonstrating ALT<2xUpper Limit of Normal (ULN), AST<2xULN, Alk Phos <=1.5xULN, bilirubin <=1.5xULN Female of non-child-bearing potential or child-bearing potential with a negative pregnancy test at screening and prepared to agree to an acceptable method of contraception Able to give written informed consent Able to read, comprehend and write at a sufficient level to complete study materials Exclusion Criteria: Current smokers or smoking history of >=10 pack years Clinically important lung condition other than asthma Diagnosis of malignancy or in the process of investigation Unstable liver disease Churg-Strauss syndrome Using methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine or any experimental anti-inflammatory therapy within 3 months of screening Omalizumab (Xolair) or any other biological for the treatment of inflammatory disease within 6 months of Visit 1 Regular use of oral or systemic corticosteroids for diseases other than asthma within 12 months or any intra-articular, short-acting intramuscular corticosteroid within 1 month or intramuscular, long-acting depot corticosteroid within 3 months Allergy/intolerance to the excipients in the mepolizumab formulation Any investigational drug within 30 days or 5 terminal half-lives, whichever is longer Pregnant or breastfeeding or planning to become pregnant Clinically significant disease which is uncontrolled with standard treatment History of alcohol misuse or substance abuse Parasitic infestation within previous 6 months Known immunodeficiency Unable to follow instructions, use the electronic diary or peak flow meter Known evidence of lack of adherence to controller medications and/or follow physician's recommendations Previous participation in a study of mepolizumab and received study medication within 90 days

Ages Eligible for Study
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Minimum Age: 12 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mepolizumab 750mg<br>Mepolizumab 750mcg i.v. every 4 weeks | Biological: Mepolizumab 750<br>* Mepolizumab 750mg every four weeks by i.v.<br>|
| Active Comparator: Mepolizumab 250mg<br>Mepolizumab 250mcg i.v. every 4 weeks | Biological: Mepolizumab 250<br>* Mepolizumab 250mg every four weeks by i.v.<br>|
| Active Comparator: Mepolizumab 75mg<br>Mepolizumab 75mcg i.v. every 4 weeks | Biological: Mepolizumab 75<br>* Mepolizumab 75mg every four weeks by i.v.<br>|
| Placebo Comparator: Placebo<br>Placebo saline every 4 weeks i.v. | Drug: Placebo saline<br>* Placebo saline every four weeks by i.v.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Clinically Significant Exacerbations of Asthma Per Year | Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for participants on maintenance oral corticosteroids [OCS], an exacerbation requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or emergency department (ED) visit. The frequency of clinically significant exacerbations of asthma over the 52-week treatment period is expressed as exacerbation rate per year. Analysis of the number of exacerbations was performed using a negative binomial regression model with covariates of treatment group, Baseline (BL) maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and BL percent (%) predicted forced expiratory volume in 1 second (FEV1), and with logarithm of time on treatment as an offset variable | From randomization (Week 0) to Week 52 or early withdrawal (EW) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Clinically Significant Exacerbation Requiring Oral or Systemic Corticosteroid, Hospitalization and/ or ED Visit | Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for participants on maintenance OCS, an exacerbation requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or ED visit. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by Week 16, Week 32 and Week 52). | From randomization (Week 0) to Week 52 or EW | 
| Number of Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visit Per Year | The frequency of exacerbations of asthma requiring hospitalization (including intubation and admittance to an intensive care unit [ICU]) or ED visit over the 52-week treatment period is expressed as exacerbation rate per year. Analysis of the number of exacerbations was performed using a negative binomial regression model with covariates of treatment group, Baseline (BL) maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and BL percent (%) predicted forced expiratory volume in 1 second (FEV1), and with logarithm of time on treatment as an offset variable. | From randomization (Week 0) to Week 52 or EW | 
| Time to First Exacerbation Requiring Hospitalization or ED Visit | Exacerbations of asthma requiring hospitalization or ED visit were assessed. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by Week 16, Week 32 and Week 52). | From randomization (Week 0) to Week 52 or EW | 
| Number of All Recorded Exacerbations Per Year | Clinically significant exacerbations (ex) of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for par. on maintenance OCS, an ex requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or ED visit. In the case, an event described as an ex was not associated with a deterioration in >=1 of the objectives of eDiary parameters, the investigator (inv) provided an explanation to support the decision for defining the event as an ex. All recorded ex were defined as those recorded by inv, regardless of the outcome of the ex review process. Analysis was performed using Negative Binomial regression model with covariates of treatment group, BL maintenance OCS therapy (OCS vs. no OCS), region, ex in the year prior to the study (as an ordinal variable) and BL % predicted FEV1, and with logarithm of time on treatment as an offset variable. | From randomization (Week 0) to Week 52 or EW | 
| Time to First All Recorded Exacerbation | All recorded exacerbations are defined as those recorded by investigators, regardless of the outcome of the exacerbation review process. In the case, an event described as an exacerbation was not associated with a deterioration in at least one of the objectives of eDiary parameters, the investigator provided an explanation to support the decision for defining the event as an exacerbation. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by week 16, week 32 and week 52). | From randomization (Week 0) to Week 52 or EW | 
| Mean Change From Baseline in Clinic Pre-bronchodilator FEV1 Over the 52-week Treatment Period | FEV1 is defined as the volume of air forcefully expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry at each clinic visit. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the Baseline value. Analysis was performed using mixed model repeated measures with covariates of Baseline, region, Baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group. | From Baseline up to Week 52 or EW | 
| Mean Change From Baseline in Clinic Post-bronchodilator FEV1 Over the 52-week Treatment Period | FEV1 is defined as the volume of air forcefully expelled from the lungs in 1 second. Post-bronchodilator FEV1 measurements were taken by spirometry at Baseline, Week 16, Week 32 and Week 52. Post bronchodilator values were recorded following reversibility testing, using the maximum post bronchodilator method. Participants unable to achieve >=12% reversibility and 200 mL change at Visit 1, reversibility test was repeated at Visit 2. These procedures to achieve the maximum post-bronchodilator are generated by the Asthma Clinical Research Network. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the Baseline value. Analysis was performed using mixed model repeated measures with covariates of Baseline, region, Baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment | From Baseline up to Week 52 or EW | 
| Mean Change From Baseline in Asthma Control Questionnaire (ACQ) Score Over the 52-week Treatment Period | The ACQ-6 is a six-item questionnaire. The six questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, shortness of breath, wheeze) and use of short-acting bronchodilator over the previous week. The response options for all these questions consist of a 0 (no impairment/limitation) to 6 (total impairment/ limitation) scale. The overall ACQ score is calculated as the mean of the 6 questions and therefore ranges between 0 (totally controlled) and 6 (severely uncontrolled). Change from BL is defined as the difference between the value of the endpoint at the time point of interest and BL value. Analysis was performed using mixed model repeated measures with covariates of BL, region, BL maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), BL % predicted FEV1, treatment and visit, plus interaction terms for visit by BL and visit by treatment group. | From Baseline up to Week 52 or EW | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose-ranging, Safety, Pharmacodynamics, eosinophils, SB-240563, Efficacy, Severe refractory asthma, mepolizumab, Placebo