Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma

NCT ID: NCT01000506

Last Updated: 2018-01-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 621 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-01
• Study Completion Date: 2012-03-23

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.

Conditions

Asthma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Mepolizumab 750mg

Mepolizumab 750mcg i.v. every 4 weeks

Group Type: ACTIVE_COMPARATOR

Mepolizumab 750

Intervention Type: BIOLOGICAL

Mepolizumab 750mg every four weeks by i.v.

Mepolizumab 250mg

Mepolizumab 250mcg i.v. every 4 weeks

Group Type: ACTIVE_COMPARATOR

Mepolizumab 250

Intervention Type: BIOLOGICAL

Mepolizumab 250mg every four weeks by i.v.

Mepolizumab 75mg

Mepolizumab 75mcg i.v. every 4 weeks

Group Type: ACTIVE_COMPARATOR

Mepolizumab 75

Intervention Type: BIOLOGICAL

Mepolizumab 75mg every four weeks by i.v.

Placebo

Placebo saline every 4 weeks i.v.

Group Type: PLACEBO_COMPARATOR

Placebo saline

Intervention Type: DRUG

Placebo saline every four weeks by i.v.

Interventions

Mepolizumab 750

Mepolizumab 750mg every four weeks by i.v.

Intervention Type: BIOLOGICAL

Mepolizumab 250

Mepolizumab 250mg every four weeks by i.v.

Intervention Type: BIOLOGICAL

Mepolizumab 75

Mepolizumab 75mg every four weeks by i.v.

Intervention Type: BIOLOGICAL

Placebo saline

Placebo saline every four weeks by i.v.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Manchester, , United Kingdom

GSK Investigational Site

Southampton, , United Kingdom

GSK Investigational Site

Long Beach, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Riverside, California, United States

GSK Investigational Site

San Diego, California, United States

GSK Investigational Site

Denver, Colorado, United States

GSK Investigational Site

New Haven, Connecticut, United States

GSK Investigational Site

Albany, Georgia, United States

GSK Investigational Site

Columbus, Georgia, United States

GSK Investigational Site

Lexington, Kentucky, United States

GSK Investigational Site

St Louis, Missouri, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Canton, Ohio, United States

GSK Investigational Site

Cleveland, Ohio, United States

GSK Investigational Site

Oklahoma City, Oklahoma, United States

GSK Investigational Site

Hershey, Pennsylvania, United States

GSK Investigational Site

Pittsburgh, Pennsylvania, United States

GSK Investigational Site

Charleston, South Carolina, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Boerne, Texas, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Madison, Wisconsin, United States

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Mendoza, , Argentina

GSK Investigational Site

San Miguel de Tucumán, , Argentina

GSK Investigational Site

New Lambton, New South Wales, Australia

GSK Investigational Site

Adelaide, South Australia, Australia

GSK Investigational Site

Clayton, Victoria, Australia

GSK Investigational Site

Melbourne, Victoria, Australia

GSK Investigational Site

Nedlands, Western Australia, Australia

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Vancouver, British Columbia, Canada

GSK Investigational Site

Mississauga, Ontario, Canada

GSK Investigational Site

Mississauga, Ontario, Canada

GSK Investigational Site

Québec, Quebec, Canada

GSK Investigational Site

Valparaíso, Región de Valparaíso, Chile

GSK Investigational Site

Puente Alto - Santiago, Región Metro de Santiago, Chile

GSK Investigational Site

Santiago, , Chile

GSK Investigational Site

Talcahuano, , Chile

GSK Investigational Site

Clamart, , France

GSK Investigational Site

Marseille, , France

GSK Investigational Site

Montpellier, , France

GSK Investigational Site

Nantes, , France

GSK Investigational Site

Saint-Pierre, , France

GSK Investigational Site

Rüdersdorf, Brandenburg, Germany

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Mainz, Rhineland-Palatinate, Germany

GSK Investigational Site

Magdeburg, Saxony-Anhalt, Germany

GSK Investigational Site

Lübeck, Schleswig-Holstein, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Bialystok, , Poland

GSK Investigational Site

Lodz, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Wroclaw, , Poland

GSK Investigational Site

Zawadzkie, , Poland

GSK Investigational Site

Zgierz, , Poland

GSK Investigational Site

Bucharest, , Romania

GSK Investigational Site

Bucharest, , Romania

GSK Investigational Site

Iași, , Romania

GSK Investigational Site

Târgu Mureş, , Romania

GSK Investigational Site

Barnaul, , Russia

GSK Investigational Site

Chelyabinsk, , Russia

GSK Investigational Site

Kazan', , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Tomsk, , Russia

GSK Investigational Site

Bucheon-si, , South Korea

GSK Investigational Site

Cheongju, Chungcheongbuk-do, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Suwon, Kyonggi-do, , South Korea

GSK Investigational Site

Cherkassy, , Ukraine

GSK Investigational Site

Dnipropetrovsk, , Ukraine

GSK Investigational Site

Dnipropetrovsk, , Ukraine

GSK Investigational Site

Dnipropetrovsk, , Ukraine

GSK Investigational Site

Donetsk, , Ukraine

GSK Investigational Site

Donetsk, , Ukraine

GSK Investigational Site

Kharkiv, , Ukraine

GSK Investigational Site

Kiev, , Ukraine

GSK Investigational Site

Kyiv, , Ukraine

GSK Investigational Site

Kyiv, , Ukraine

GSK Investigational Site

Mykolayiv, , Ukraine

GSK Investigational Site

Leicester, Leicestershire, United Kingdom

GSK Investigational Site

London, , United Kingdom

Countries

United States; Argentina; Australia; Canada; Chile; France; Germany; Poland; Romania; Russia; South Korea; Ukraine; United Kingdom

References

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18;380(9842):651-9. doi: 10.1016/S0140-6736(12)60988-X.

Reference Type: BACKGROUND

PMID: 22901886 (View on PubMed)

Chen W, Reddel HK, FitzGerald JM, Beasley R, Janson C, Sadatsafavi M. Can we predict who will benefit most from biologics in severe asthma? A post-hoc analysis of two phase 3 trials. Respir Res. 2023 May 2;24(1):120. doi: 10.1186/s12931-023-02409-2.

Reference Type: DERIVED

PMID: 37131185 (View on PubMed)

Gibson PG, Prazma CM, Chupp GL, Bradford ES, Forshag M, Mallett SA, Yancey SW, Smith SG, Bel EH. Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions. Respir Res. 2021 Jun 7;22(1):171. doi: 10.1186/s12931-021-01746-4.

Reference Type: DERIVED

PMID: 34098955 (View on PubMed)

Kim MK, Park HS, Park CS, Min SJ, Albers FC, Yancey SW, Mayer B, Kwon N. Efficacy and safety of mepolizumab in Korean patients with severe eosinophilic asthma from the DREAM and MENSA studies. Korean J Intern Med. 2021 Mar;36(2):362-370. doi: 10.3904/kjim.2019.198. Epub 2020 May 26.

Reference Type: DERIVED

PMID: 32450626 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30954640 (View on PubMed)

Ortega H, Yancey SW, Keene ON, Gunsoy NB, Albers FC, Howarth PH. Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):980-986.e1. doi: 10.1016/j.jaip.2017.12.019. Epub 2018 Feb 15.

Reference Type: DERIVED

PMID: 29398640 (View on PubMed)

Gunsoy NB, Cockle SM, Yancey SW, Keene ON, Bradford ES, Albers FC, Pavord ID. Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):874-882.e4. doi: 10.1016/j.jaip.2017.11.026. Epub 2017 Dec 16.

Reference Type: DERIVED

PMID: 29258789 (View on PubMed)

Ortega H, Li H, Suruki R, Albers F, Gordon D, Yancey S. Cluster analysis and characterization of response to mepolizumab. A step closer to personalized medicine for patients with severe asthma. Ann Am Thorac Soc. 2014 Sep;11(7):1011-7. doi: 10.1513/AnnalsATS.201312-454OC.

Reference Type: DERIVED

PMID: 24983709 (View on PubMed)

Prazma CM, Wenzel S, Barnes N, Douglass JA, Hartley BF, Ortega H. Characterisation of an OCS-dependent severe asthma population treated with mepolizumab. Thorax. 2014 Dec;69(12):1141-2. doi: 10.1136/thoraxjnl-2014-205581. Epub 2014 May 16.

Reference Type: DERIVED

PMID: 24834924 (View on PubMed)

Study Documents

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

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Other Identifiers

112997

Identifier Type: -

Identifier Source: org_study_id