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
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 621
- Locations
- 1
- Primary Endpoint
- Number of Clinically Significant Exacerbations of Asthma Per Year
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 12 Years to 65 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Mepolizumab 750mg
Mepolizumab 750mcg i.v. every 4 weeks
Intervention: Mepolizumab 750 (Biological)
Mepolizumab 250mg
Mepolizumab 250mcg i.v. every 4 weeks
Intervention: Mepolizumab 250 (Biological)
Mepolizumab 75mg
Mepolizumab 75mcg i.v. every 4 weeks
Intervention: Mepolizumab 75 (Biological)
Placebo
Placebo saline every 4 weeks i.v.
Intervention: Placebo saline (Drug)
Outcomes
Primary Outcomes
Number of Clinically Significant Exacerbations of Asthma Per Year
Time Frame: From randomization (Week 0) to Week 52 or early withdrawal (EW)
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
Secondary Outcomes
- Time to First Clinically Significant Exacerbation Requiring Oral or Systemic Corticosteroid, Hospitalization and/ or ED Visit(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(From randomization (Week 0) to Week 52 or EW)
- Mean Change From Baseline in Asthma Control Questionnaire (ACQ) Score Over the 52-week Treatment Period(From Baseline up to Week 52 or EW)
- Time to First All Recorded Exacerbation(From randomization (Week 0) to Week 52 or EW)
- Time to First Exacerbation Requiring Hospitalization or ED Visit(From randomization (Week 0) to Week 52 or EW)
- Number of All Recorded Exacerbations Per Year(From randomization (Week 0) to Week 52 or EW)
- Mean Change From Baseline in Clinic Post-bronchodilator FEV1 Over the 52-week Treatment Period(From Baseline up to Week 52 or EW)
- Mean Change From Baseline in Clinic Pre-bronchodilator FEV1 Over the 52-week Treatment Period(From Baseline up to Week 52 or EW)