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

NCT ID: NCT01691521

Last Updated: 2018-08-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 580 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-08
• Study Completion Date: 2014-01-18

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.

Conditions

Asthma

Study Design

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

Study Groups

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)

Group Type: EXPERIMENTAL

Mepolizumab IV

Intervention Type: DRUG

Mepolizumab 75 mg IV will be administered every 4 weeks with the last dose at Week 28

SC Placebo

Intervention Type: DRUG

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

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)

Group Type: EXPERIMENTAL

Mepolizumab SC

Intervention Type: DRUG

Mepolizumab 100 mg SC will be administered every 4 weeks with the last dose at Week 28

IV Placebo

Intervention Type: DRUG

Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28

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)

Group Type: PLACEBO_COMPARATOR

IV Placebo

Intervention Type: DRUG

Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28

SC Placebo

Intervention Type: DRUG

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

Interventions

Mepolizumab IV

Mepolizumab 75 mg IV will be administered every 4 weeks with the last dose at Week 28

Intervention Type: DRUG

Mepolizumab SC

Mepolizumab 100 mg SC will be administered every 4 weeks with the last dose at Week 28

Intervention Type: DRUG

IV Placebo

Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28

Intervention Type: DRUG

SC Placebo

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

Intervention Type: DRUG

Eligibility 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)

• Minimum Eligible Age: 12 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

Birmingham, Alabama, United States

GSK Investigational Site

Newport Beach, California, United States

GSK Investigational Site

Riverside, California, United States

GSK Investigational Site

Rolling Hills Estates, 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

Chicago, Illinois, United States

GSK Investigational Site

Baltimore, Maryland, United States

GSK Investigational Site

Rochester, Minnesota, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Rochester, New York, United States

GSK Investigational Site

Durham, North Carolina, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Cincinnati, Ohio, United States

GSK Investigational Site

Cincinnati, Ohio, United States

GSK Investigational Site

Cleveland, Ohio, United States

GSK Investigational Site

Columbus, Ohio, United States

GSK Investigational Site

Hershey, Pennsylvania, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Salt Lake City, Utah, United States

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

San Rafael, Mendoza Province, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Mendoza, , Argentina

GSK Investigational Site

New Lambton, New South Wales, Australia

GSK Investigational Site

Bedford Park, South Australia, Australia

GSK Investigational Site

Clayton, Victoria, Australia

GSK Investigational Site

Nedlands, Western Australia, Australia

GSK Investigational Site

Parkville, , Australia

GSK Investigational Site

Brussels, , Belgium

GSK Investigational Site

Ghent, , Belgium

GSK Investigational Site

Leuven, , Belgium

GSK Investigational Site

Liège, , Belgium

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Edmonton, Alberta, Canada

GSK Investigational Site

Vancouver, British Columbia, Canada

GSK Investigational Site

Winnipeg, Manitoba, Canada

GSK Investigational Site

Burlington, Ontario, Canada

GSK Investigational Site

Hamilton, Ontario, Canada

GSK Investigational Site

Windsor, Ontario, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Québec, Quebec, Canada

GSK Investigational Site

Saint-Charles-Borromée, Quebec, Canada

GSK Investigational Site

Trois-Rivières, Quebec, Canada

GSK Investigational Site

Rancagua, Reg Del Libert Bern Ohiggins, Chile

GSK Investigational Site

Santiago, , Chile

GSK Investigational Site

Talcahuano, , Chile

GSK Investigational Site

Le Kremlin-Bicêtre, , France

GSK Investigational Site

Lille, , France

GSK Investigational Site

Lyon, , France

GSK Investigational Site

Marseille, , France

GSK Investigational Site

Montpellier, , France

GSK Investigational Site

Perpignan, , France

GSK Investigational Site

Saint-Pierre, , France

GSK Investigational Site

Aschaffenburg, Bavaria, Germany

GSK Investigational Site

Potsdam, Brandenburg, Germany

GSK Investigational Site

Rüdersdorf, Brandenburg, Germany

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Gelnhausen, Hesse, Germany

GSK Investigational Site

Neu-Isenburg, Hesse, Germany

GSK Investigational Site

Mainz, Rhineland-Palatinate, Germany

GSK Investigational Site

Magdeburg, Saxony-Anhalt, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Hamburg, , Germany

GSK Investigational Site

Foggia, Apulia, Italy

GSK Investigational Site

Napoli, Campania, Italy

GSK Investigational Site

Parma, Emilia-Romagna, Italy

GSK Investigational Site

Genoa, Liguria, Italy

GSK Investigational Site

Pietra Ligure (SV), Liguria, Italy

GSK Investigational Site

Pisa, Tuscany, Italy

GSK Investigational Site

Perugia, Umbria, Italy

GSK Investigational Site

Cittadella PD, Veneto, Italy

GSK Investigational Site

Chiba, , Japan

GSK Investigational Site

Fukuoka, , Japan

GSK Investigational Site

Fukuoka, , Japan

GSK Investigational Site

Fukuoka, , Japan

GSK Investigational Site

Gunma, , Japan

GSK Investigational Site

Hiroshima, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hyōgo, , Japan

GSK Investigational Site

Hyōgo, , Japan

GSK Investigational Site

Ibaraki, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Kumamoto, , Japan

GSK Investigational Site

Mie, , Japan

GSK Investigational Site

Okinawa, , Japan

GSK Investigational Site

Okinawa, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Zapopan, Jalisco, Mexico

GSK Investigational Site

Zapopan, Jalisco, Mexico

GSK Investigational Site

Monterrey, Nuevo León, Mexico

GSK Investigational Site

México DF, , Mexico

GSK Investigational Site

Chelyabinsk, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Anyang-si, , South Korea

GSK Investigational Site

Bucheon-si, , South Korea

GSK Investigational Site

Cheongju, Chungcheongbuk-do, , South Korea

GSK Investigational Site

Daegu, , South Korea

GSK Investigational Site

Donggu Gwangju, , South Korea

GSK Investigational Site

Incheon, , South Korea

GSK Investigational Site

Jeonju-si, Jeollabuk-Do, , South Korea

GSK Investigational Site

Kangwon-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

Alicante, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Pozuelo de Alarcón/Madrid, , Spain

GSK Investigational Site

Kharkiv, , Ukraine

GSK Investigational Site

Kiev, , Ukraine

GSK Investigational Site

Mykolayiv, , Ukraine

GSK Investigational Site

Vinnytsia, , Ukraine

GSK Investigational Site

Bradford, , United Kingdom

GSK Investigational Site

Glasgow, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Plymouth, , United Kingdom

GSK Investigational Site

Southampton, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Canada; Chile; France; Germany; Italy; Japan; Mexico; Russia; South Korea; Spain; Ukraine; United Kingdom

References

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)

Lemiere C, Taille C, Lee JK, Smith SG, Mallett S, Albers FC, Bradford ES, Yancey SW, Liu MC. Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials. Respir Res. 2021 Jun 22;22(1):184. doi: 10.1186/s12931-021-01767-z.

Reference Type: DERIVED

PMID: 34158028 (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)

Best N, Price RG, Pouliquen IJ, Keene ON. Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing. Pharm Stat. 2021 May;20(3):551-562. doi: 10.1002/pst.2093. Epub 2021 Jan 21.

Reference Type: DERIVED

PMID: 33475231 (View on PubMed)

Wardlaw A, Howarth PH, Israel E, Taille C, Quirce S, Mallett S, Bates S, Albers FC, Kwon N. Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma. Clin Exp Allergy. 2020 Jul;50(7):869-872. doi: 10.1111/cea.13680. Epub 2020 Jun 25. No abstract available.

Reference Type: DERIVED

PMID: 32515118 (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)

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.

Reference Type: DERIVED

PMID: 31447130 (View on PubMed)

Khurana S, Lyness JM, Mallett S, Nelsen LM, Prazma CM, Albers FC, Forshag M, Llanos JP, Yancey SW, Ortega HG. Association of depressive symptoms with health status and markers of uncontrolled severe asthma. Allergy Asthma Proc. 2019 Jul 1;40(4):230-239. doi: 10.2500/aap.2019.40.4229.

Reference Type: DERIVED

PMID: 31262378 (View on PubMed)

Nelsen LM, Cockle SM, Gunsoy NB, Jones P, Albers FC, Bradford ES, Mullerova H. Impact of exacerbations on St George's Respiratory Questionnaire score in patients with severe asthma: post hoc analyses of two clinical trials and an observational study. J Asthma. 2020 Sep;57(9):1006-1016. doi: 10.1080/02770903.2019.1630640. Epub 2019 Jun 28.

Reference Type: DERIVED

PMID: 31251094 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31047111 (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, Menzies-Gow A, Llanos JP, Forshag M, Albers F, Gunsoy N, Bradford ES, Yancey SW, Kraft M. Rapid and Consistent Improvements in Morning PEF in Patients with Severe Eosinophilic Asthma Treated with Mepolizumab. Adv Ther. 2018 Jul;35(7):1059-1068. doi: 10.1007/s12325-018-0727-8. Epub 2018 Jun 15.

Reference Type: DERIVED

PMID: 29949045 (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)

Albers FC, Price RG, Smith SG, Yancey SW. Mepolizumab efficacy in patients with severe eosinophilic asthma receiving different controller therapies. J Allergy Clin Immunol. 2017 Nov;140(5):1464-1466.e4. doi: 10.1016/j.jaci.2017.06.010. Epub 2017 Jul 4. No abstract available.

Reference Type: DERIVED

PMID: 28687231 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27087007 (View on PubMed)

Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1198-207. doi: 10.1056/NEJMoa1403290. Epub 2014 Sep 8.

Reference Type: DERIVED

PMID: 25199059 (View on PubMed)

Study Documents

Document Type: Informed Consent Form

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

View Document

Document Type: Annotated Case Report 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: Clinical Study Report

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

View Document

Document Type: Individual Participant Data Set

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

View Document

Document Type: Dataset Specification

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

View Document

Related Links

https://www.clinicalstudydatarequest.com

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Other Identifiers

115588

Identifier Type: -

Identifier Source: org_study_id