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NCT01691521

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

Completed Phase 3 Results posted Last updated 6 August 2018
What this trial tests

Phase 3 trial testing Mepolizumab IV in Asthma in 580 participants. Completed in 18 January 2014.

Timeline
8 October 2012
Primary endpoint
1 January 2014
18 January 2014

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingdouble
Primary purposetreatment
Enrollment580
Start date8 October 2012
Primary completion1 January 2014
Estimated completion18 January 2014
Sites134 locations across France, Italy, Japan, Russia, Ukraine, Belgium, Chile, United Kingdom

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

12 and older, any sex, with Asthma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Clinically Significant Exacerbations of Asthma Per Year Primary · 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. Anal

GroupValue95% CI
Placebo1.74
Mepolizumab 75 mg IV0.93
Mepolizumab 100 mg SC0.83
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year Secondary · 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. Anal

GroupValue95% CI
Placebo0.20
Mepolizumab 75 mg IV0.14
Mepolizumab 100 mg SC0.08
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year Secondary · 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 perfo

GroupValue95% CI
Placebo0.10
Mepolizumab 75 mg IV0.06
Mepolizumab 100 mg SC0.03
Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 Secondary · 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.

GroupValue95% CI
Placebo86± 31.4
Mepolizumab 75 mg IV186± 31.5
Mepolizumab 100 mg SC183± 31.1
Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 Secondary · 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 defin

GroupValue95% CI
Placebo-9.0± 1.16
Mepolizumab 75 mg IV-15.4± 1.16
Mepolizumab 100 mg SC-16.0± 1.13

Adverse events — posted to ClinicalTrials.gov

Time frame: On-treatment serious adverse events (SAEs) and non-serious AEs were defined as events occurring from the first dose of investigational product until 28 days after the last dose of investigational product, up to 32 weeks.. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 27/191 (14%)
Deaths:
Mepolizumab 75 mg IV
Serious: 14/191 (7%)
Deaths:
Mepolizumab 100 mg SC
Serious: 16/194 (8%)
Deaths:

Serious adverse events (40 terms)

ReactionSystemPlaceboMepolizumab 75 mg IVMepolizumab 100 mg SC
AsthmaRespiratory, thoracic and mediastinal disorders
BronchitisInfections and infestations
Herpes zosterInfections and infestations
Pulmonary fibrosisRespiratory, thoracic and mediastinal disorders
Clostridium difficile infectionInfections and infestations
Croup infectiousInfections and infestations
DiverticulitisInfections and infestations
InfluenzaInfections and infestations
PneumoniaInfections and infestations
Postoperative wound infectionInfections and infestations
UrosepsisInfections and infestations
Viral upper respiratory tract infectionInfections and infestations
Vulval abscessInfections and infestations
ContusionInjury, poisoning and procedural complications
Fractured coccyxInjury, poisoning and procedural complications
Heat strokeInjury, poisoning and procedural complications
Inflammation of woundInjury, poisoning and procedural complications
Rib fractureInjury, poisoning and procedural complications
Road traffic accidentInjury, poisoning and procedural complications
Tendon ruptureInjury, poisoning and procedural complications
NephrolithiasisRenal and urinary disorders
Calculus uretericRenal and urinary disorders
Calculus urethralRenal and urinary disorders
Nephrogenic diabetes insipidusRenal and urinary disorders
Renal colicRenal and urinary disorders
Other adverse events (31 terms — click to expand)

ReactionSystemPlaceboMepolizumab 75 mg IVMepolizumab 100 mg SC
NasopharyngitisInfections and infestations
HeadacheNervous system disorders
Upper respiratory tract infectionInfections and infestations
SinusitisInfections and infestations
Injection site reactionGeneral disorders
BronchitisInfections and infestations
AsthmaRespiratory, thoracic and mediastinal disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
GastroenteritisInfections and infestations
Pain in extremityMusculoskeletal and connective tissue disorders
InfluenzaInfections and infestations
CoughRespiratory, thoracic and mediastinal disorders
FatigueGeneral disorders
EczemaSkin and subcutaneous tissue disorders
DizzinessNervous system disorders
NauseaGastrointestinal disorders
Urinary tract infectionInfections and infestations
Abdominal pain upperGastrointestinal disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
RhinitisInfections and infestations
PharyngitisInfections and infestations
HypertensionVascular disorders
MigraineNervous system disorders
MyalgiaMusculoskeletal and connective tissue disorders
Rhinitis allergicRespiratory, thoracic and mediastinal disorders
HypersensitivityImmune system disorders
ToothacheGastrointestinal disorders

Most-reported serious reactions: Asthma, Bronchitis, Herpes zoster, Pulmonary fibrosis, Clostridium difficile infection, Croup infectious, Diverticulitis, Influenza.

Data from ClinicalTrials.gov NCT01691521 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Mepolizumab treatment in patients with severe eosinophilic asthma.
    Ortega HG, Liu MC, Pavord ID, Brusselle GG, et al · · 2014 · cited 1593× · PMID 25199059 · DOI 10.1056/nejmoa1403290
  2. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.
    Ortega HG, Yancey SW, Mayer B, Gunsoy NB, et al · · 2016 · cited 398× · PMID 27177493 · DOI 10.1016/s2213-2600(16)30031-5
  3. Long-term Efficacy and Safety of Mepolizumab in Patients With Severe Eosinophilic Asthma: A Multi-center, Open-label, Phase IIIb Study.
    Lugogo N, Domingo C, Chanez P, Leigh R, et al · · 2016 · cited 197× · PMID 27553751 · DOI 10.1016/j.clinthera.2016.07.010
  4. Antibodies to watch in 2015.
    Reichert JM. · · 2015 · cited 117× · PMID 25484055 · DOI 10.4161/19420862.2015.988944
  5. The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma.
    Chapman KR, Albers FC, Chipps B, Muñoz X, et al · · 2019 · cited 113× · PMID 31049972 · DOI 10.1111/all.13850
  6. Real-world mepolizumab in the prospective severe asthma REALITI-A study: initial analysis.
    Harrison T, Canonica GW, Chupp G, Lee J, et al · · 2020 · cited 101× · PMID 32817259 · DOI 10.1183/13993003.00151-2020
  7. Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment.
    Magnan A, Bourdin A, Prazma CM, Albers FC, et al · · 2016 · cited 74× · PMID 27087007 · DOI 10.1111/all.12914
  8. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease.
    Durham AL, Caramori G, Chung KF, Adcock IM. · · 2016 · cited 74× · PMID 26334389 · DOI 10.1016/j.trsl.2015.08.004

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