Clinical trial NCT01691508: Mepolizumab Steroid-Sparing Study in Subjects With Severe Refractory Asthma
Official title: MEA115575: A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of Mepolizumab Adjunctive Therapy to Reduce Steroid Use in Subjects With Severe Refractory Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Safety
Steroid Reduction
Efficacy
SB-240563
Eosinophils
Quality of Life
Mepolizumab
Severe Refractory Asthma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-09-24
Enrollment: 135
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised, double-blind, placebo-controlled, parallel-group, multicenter study of mepolizumab in comparison with placebo in reducing Oral Corticosteroid (OCS) use in subjects with severe refractory asthma. The study consists of four phases, OCS Optimisation Phase (Week -8 to Week 0), and the double-blind treatment period divided into an Induction Phase (Week 0 to Week 4), OCS Reduction Phase (Week 5 upto Week 20) followed by Maintenance Phase (Week 20 to Week 24). During the Optimisation Phase the investigator will adjust the OCS (prednisone/prednisolone) dose according to the Optimisation titration schedule based on a review of Asthma Control Questionnaire (ACQ)-5 score and exacerbation. In the Induction Phase subjects will be randomized 1:1 (approximately 60 per arm) to receive either mepolizumab (100 mg) administered subcutaneously (SC) or placebo every 4 weeks in addition to their existing maintenance asthma therapy with the lowest dose of OCS from Optimisation Phase. The Induction Phase will allow sufficient time for those subjects randomised to the mepolizumab arm to achieve a decrease in the eosinophilic inflammation prior to the reduction in OCS. During the Reduction Phase, subjects will continue receiving 100 mg mepolizumab/placebo every 4 weeks and the OCS dose reduction will be done every 4 weeks using the reduction titration schedule based on a review of eDiary parameters recorded by the subject, the subjects' exacerbation history, and a review of the signs and symptoms of adrenal insufficiency. In the Maintenance Phase subjects will be maintained without any further OCS dose adjustment. Subjects who complete the 24 week double-blind period and meet the eligibility criteria, will be offered the opportunity to participate in an open label extension (OLE) study otherwise they will return for a Follow-up Visit 12 weeks after their last dose of double blind study treatment. At each clinic visit, adverse events, safety labs, spirometery parameters and exacerbations will be assessed. The pharmacokinetic samples will be collected in the beginning of the treatment, prior to last dose, at the end of study (exit visit) and the follow up.


Eligibility criteria: Inclusion Criteria:

* Informed Consent and Study Compliance: Subjects must be able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form.
* Systemic Corticosteroids: Requirement for regular treatment with maintenance systemic corticosteroids in the 6 months prior to Visit 1 and using a stable oral corticosteroid dose for 4 weeks prior to Visit 1. Subjects must be taking 5.0 to 35 mg/day of prednisone or equivalent at Visit 1 and must agree to switch to study required prednisone/prednisolone as their oral corticosteroid and use it per protocol for the duration of the study.
* Inhaled Corticosteroids: Requirement for regular treatment with high dose inhaled corticosteroid in the 6 months prior to Visit 1. For 18 years of age and older: inhaled corticosteroid (ICS) dose must be \>=880 microgram (µg)/day fluticasone propionate (FP) (ex-actuator) or equivalent daily. For ICS/ long acting beta2 agonist (LABA) combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion. For ages 12 to 17: ICS dose must be \>=440 μg/day FP (ex-actuator) or equivalent daily.
* Controller Medication: Current treatment with an additional controller medication for at least 3 months OR documentation of having used and failed an additional controller medication for at least 3 successive months during the prior 12 months \[e.g., LABA, leukotriene receptor antagonist (LTRA), or theophylline\].
* Eosinophilic Asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma.
* FEV1: Persistent airflow obstruction as indicated by a pre-bronchodilator FEV1 \<80% predicted.
* Asthma: Evidence of asthma indicated by airway reversibility, hyperresponsiveness or airway variability.

Exclusion Criteria:

* Smoking history: Current smokers or former smokers with a smoking history of \>=10 pack years.
* Concurrent Respiratory Disease: Presence of a clinically important lung condition other than asthma.
* Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening
* Liver Disease: Unstable liver disease
* Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment.
* Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
* Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosiniophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic Esophaghitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.
* ECG: ECG assessment QTcF \>=450 milliseconds (msec) or QTcF \>= 480 msec for subjects with Bundle Branch Block.
* Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus - HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.
* Omalizumab Use: Subjects who have received omalizumab \[Xolair\] within 130 days of Visit 1.
* Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.
* Investigational Medications: 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, prior to Visit 1 (this also includes investigational formulations of marketed products).
* Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic.
* Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.
* Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
* Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
* Previous participation: Subjects who have previously any study of mepolizumab and received Investigational Product.

Primary outcomes:
measure: Number of Participants With the Indicated Percent Reduction From Baseline in Oral Corticosteroid (OCS) Dose During Weeks 20 to 24 While Maintaining Asthma Control
timeFrame: Baseline; Weeks 20 to 24
Secondary outcomes:
measure: Number of Participants Who Achieved a Reduction of >=50% in Their Daily Oral Corticosteroid (OCS) Dose Compared With Baseline Dose, During Weeks 20 to 24 While Maintaining Asthma Control
timeFrame: Baseline; Weeks 20 to 24
measure: Number of Participants Who Achieved a Reduction of Their Daily OCS Dose to <=5.0 mg During Weeks 20 to 24 While Maintaining Asthma Control
timeFrame: Weeks 20 to 24
measure: Number of Participants Who Achieved a Total Reduction of OCS Dose During Weeks 20 to 24 While Maintaining Asthma Control
timeFrame: Weeks 20 to 24
measure: Median Percentage Change From Baseline in Daily OCS Dose During Weeks 20 to 24 While Maintaining Asthma Control
timeFrame: Baseline; Weeks 20 to 24
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Pittsburg
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: New Lambton
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Bedford Park
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec City
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Brno
country: Czech Republic
facility: GSK Investigational Site
city: Olomouc
country: Czech Republic
facility: GSK Investigational Site
city: Praha 4
country: Czech Republic
facility: GSK Investigational Site
city: Praha 8
country: Czech Republic
facility: GSK Investigational Site
city: Gières
country: France
facility: GSK Investigational Site
city: Montpellier cedex 5
country: France
facility: GSK Investigational Site
city: Nantes cedex 1
country: France
facility: GSK Investigational Site
city: Paris Cedex 18
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Potsdam
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Ruedersdorf
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Gelnhausen
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Neu isenburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Luebeck
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Leeuwarden
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
state: Leicestershire
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Casale TB, Burnette A, Bourdin A, Howarth P, Hahn B, Stach-Klysh A, Khurana S. Oral corticosteroid-sparing effects of mepolizumab in severe eosinophilic asthma: evidence from randomized controlled trials and real-world studies. Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221107313. doi: 10.1177/17534666221107313.
citation: Khurana S, Brusselle GG, Bel EH, FitzGerald JM, Masoli M, Korn S, Kato M, Albers FC, Bradford ES, Gilson MJ, Price RG, Humbert M. Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study. Clin Ther. 2019 Oct;41(10):2041-2056.e5. doi: 10.1016/j.clinthera.2019.07.007. Epub 2019 Aug 22.
citation: Yancey SW, Bradford ES, Keene ON. Disease burden and efficacy of mepolizumab in patients with severe asthma and blood eosinophil counts of >/=150-300 cells/muL. Respir Med. 2019 May;151:139-141. doi: 10.1016/j.rmed.2019.04.008. Epub 2019 Apr 8.
citation: Ortega HG, Meyer E, Brusselle G, Asano K, Prazma CM, Albers FC, Mallett SA, Yancey SW, Gleich GJ. Update on immunogenicity in severe asthma: Experience with mepolizumab. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2469-2475.e1. doi: 10.1016/j.jaip.2019.03.042. Epub 2019 Apr 5. No abstract available.
citation: Keene ON. Strategies for composite estimands in confirmatory clinical trials: Examples from trials in nasal polyps and steroid reduction. Pharm Stat. 2019 Jan;18(1):78-84. doi: 10.1002/pst.1909. Epub 2018 Oct 29.
citation: Magnan A, Bourdin A, Prazma CM, Albers FC, Price RG, Yancey SW, Ortega H. Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment. Allergy. 2016 Sep;71(9):1335-44. doi: 10.1111/all.12914. Epub 2016 May 24.
citation: Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1189-97. doi: 10.1056/NEJMoa1403291. Epub 2014 Sep 8.