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Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma

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ClinicalTrials.gov Identifier: NCT01691521
Recruitment Status : Completed
First Posted : September 24, 2012
Results First Posted : January 26, 2016
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Description
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Brief Summary:

This study will evaluate two dose regimens of mepolizumab [75mg intravenous (i.v.) or 100mg subcutaneous (SC) every 4 weeks] compared with placebo over a 32 week treatment period in subjects with severe refractory asthma with elevated blood eosinophils. Efficacy will be measured by a reduction in the frequency of asthma exacerbations. Additional efficacy assessments will include measurements of lung function, symptom scores, and quality of life. Safety will be assessed by clinical laboratory samples, ECGs, immunogenicity and adverse events.

This study is intended to replicate the Phase IIb/III study MEA112997. Subjects in MEA115588, who meet all eligibility criteria at screening visit, will enter the run-in period. Those subjects that are not able/eligible to be randomised at the end of the 6 week run-in period will be deemed run-in failures. Subjects will remain on their current maintenance therapy throughout the run-in, double-blind treatment administration and follow-up periods. Subjects who meet the randomisation eligibility criteria will be randomised in a 1:1:1 ratio to receive one of the following treatments every 4 weeks for a total of 8 doses: Mepolizumab 75 miligram (mg) i.v. and placebo SC, or Mepolizumab 100 mg SC and placebo i.v. or Placebo i.v. and placebo SC.

Subjects that receive all 8 doses of double-blind treatment, and meet the eligibility criteria for the Open-Label Extension (OLE) Study, will be offered the opportunity to participate in the OLE trial.


Condition or disease Intervention/treatment Phase
Asthma Drug: Mepolizumab IV Drug: Mepolizumab SC Drug: IV Placebo Drug: SC Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 580 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: MEA115588 A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel-group, Multi-centre Study of the Efficacy and Safety of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma
Study Start Date : October 8, 2012
Actual Primary Completion Date : January 1, 2014
Actual Study Completion Date : January 18, 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
Drug Information available for: Mepolizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Mepolizumab IV
Mepolizumab 75 mg will be administered intravenously approximately every 4 weeks with the last dose at week 32. Subjects in the Mepolizumab IV arm will receive mepolizumab 75 mg intravenously and placebo SC once every 4 weeks with the last dose at Week 28 (total of 8 doses)
 Drug: Mepolizumab IV
Mepolizumab 75 mg IV will be administered every 4 weeks with the last dose at Week 28

Drug: SC Placebo
Normal saline (placebo) will be administered SC every 4 weeks with the last dose at Week 28
Experimental: Mepolizumab SC
Subjects in the Mepolizumab SC arm will receive mepolizumab 100 mg SC and placebo IV once every 4 weeks with the last dose at Week 28 (total of 8 doses)
 Drug: Mepolizumab SC
Mepolizumab 100 mg SC will be administered every 4 weeks with the last dose at Week 28

Drug: IV Placebo
Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28
Placebo Comparator: Placebo
Subjects in the Placebo arm will receive matching placebo SC and placebo IV once every 4 weeks with the last dose at Week 28 (total of 8 doses)
 Drug: IV Placebo
Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28

Drug: SC Placebo
Normal saline (placebo) will be administered SC every 4 weeks with the last dose at Week 28


Outcome Measures
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Primary Outcome Measures :
  1. Number of Clinically Significant Exacerbations of Asthma Per Year [ Time Frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose ]
    Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.


Secondary Outcome Measures :
  1. Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year [ Time Frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose ]
    Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.

  2. Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year [ Time Frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose ]
    Clinically significant exacerbations of asthma is defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.

  3. Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 [ Time Frame: Baseline, Week 32 ]
    FEV1 is defined as the volume of air expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry. 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 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.

  4. Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 [ Time Frame: Baseline, Week 32 ]
    The St. George's Respiratory Questionnaire is an established instrument, comprising 50 questions, evaluating symptoms, activity, and impacts; to measure Quality of Life in participants with diseases of airway obstruction and to elicit the participant's opinion of his/her health. The lowest possible value is zero and the highest possible value is 100. The higher values correspond to greater impairment in quality of life. The questionnaire was administered at Baseline (Visit 2) and at the Exit Visit (approximately 4 weeks after the last dose of study treatment). 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 performed using analysis of covariance 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), baseline % predicted FEV1, and treatment.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to give written informed consent prior to participation in the study
  • At least 12 years of age at visit 1 and a minimum weight of 45 kilogram (kg)
  • A well-documented requirement for regular treatment with high dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS)
  • Current treatment with an additional controller medication, besides ICS, for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months
  • Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma
  • At Visit 1, a pre-bronchodilator FEV1 <80% (for subjects >= 18 years of age), a pre-bronchodilator FEV1 <90% or FEV1:FVC ratio <0.8 (for subjects 12-17 years of age).
  • Previously confirmed history of two or more exacerbations requiring treatment with systemic CS
  • Male or Eligible Female (females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control)
  • French subjects will be included only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

  • Current smokers or former smokers with a smoking history of >=10 pack years
  • Presence of a known pre-existing, clinically important lung condition other than asthma
  • A current malignancy or previous history of malignancy in less than 12 months
  • Known, pre-existing, unstable liver disease cirrhosis and known biliary abnormalities
  • Known, pre-existing severe or clinically significant cardiovascular disease
  • known, pre-existing other concurrent clinically significant medical conditions that are uncontrolled with standard treatment
  • Subjects with any eosinophilic diseases
  • QTc(F) ≥450msec or QTc(F) ≥480 msec
  • A history of alcohol/substance abuse
  • Subject with known immunodeficiency
  • Subjects who have received omalizumab within 130 days of Visit 1 or any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1
  • Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer
  • Subjects with allergy/intolerance to a monoclonal antibody or biologic.
  • Subjects who are pregnant or breastfeeding
  • Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations
  • Previously participated in any study with mepolizumab and received investigational product (including placebo)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01691521


Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
More Information
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Additional Information:

Study Data/Documents: Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 115588
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01691521    
Other Study ID Numbers: 115588
First Posted: September 24, 2012    Key Record Dates
Results First Posted: January 26, 2016
Last Update Posted: August 6, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Keywords provided by GlaxoSmithKline:
safety
SB-240563
efficacy
placebo
 eosinophils
mepolizumab
Severe refractory asthma
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
 Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases