Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma

Phase 2

Completed

Conditions: Asthma

Interventions: Biological: Mepolizumab 75
Biological: Mepolizumab 250
Drug: Placebo saline
Biological: Mepolizumab 750

Registration Number: NCT01000506

Lead Sponsor: GlaxoSmithKline

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 621

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mepolizumab 75mg	Mepolizumab 75	Mepolizumab 75mcg i.v. every 4 weeks
Mepolizumab 250mg	Mepolizumab 250	Mepolizumab 250mcg i.v. every 4 weeks
Placebo	Placebo saline	Placebo saline every 4 weeks i.v.
Mepolizumab 750mg	Mepolizumab 750	Mepolizumab 750mcg i.v. every 4 weeks

Primary Outcome Measures

Name	Time	Method
Number of Clinically Significant Exacerbations of Asthma Per Year	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 Outcome Measures

Name	Time	Method
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	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).
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	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.
Mean Change From Baseline in Asthma Control Questionnaire (ACQ) Score Over the 52-week Treatment Period	From Baseline up to Week 52 or EW	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.
Time to First All Recorded Exacerbation	From randomization (Week 0) to Week 52 or EW	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).
Time to First Exacerbation Requiring Hospitalization or ED Visit	From randomization (Week 0) to Week 52 or EW	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).
Number of All Recorded Exacerbations Per Year	From randomization (Week 0) to Week 52 or EW	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.
Mean Change From Baseline in Clinic Post-bronchodilator FEV1 Over the 52-week Treatment Period	From Baseline up to Week 52 or EW	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
Mean Change From Baseline in Clinic Pre-bronchodilator FEV1 Over the 52-week Treatment Period	From Baseline up to Week 52 or EW	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.