Mepolizumab Steroid-Sparing Study in Subjects With Severe Refractory Asthma

NCT ID: NCT01691508

Last Updated: 2017-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 135 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2013-12-31

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.

Conditions

Asthma

Study Design

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

Study Groups

Mepolizumab

Mepolizumab 100 mg subcutaneous once every 4 weeks upto Week 20

Group Type: EXPERIMENTAL

Mepolizumab

Intervention Type: DRUG

Mepolizumab is a fully humanised Immunoglobulin G antibody (IgG1, kappa) with human heavy and light chain frameworks.

OCS (prednisone/prednisolone)

Intervention Type: DRUG

Oral Corticosteroid (prednisone/prednisolone)

Placebo

Placebo subcutaneous once every 4 weeks upto Week 20

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Will be available as an equivalent volume of 0.9% sodium chloride.

OCS (prednisone/prednisolone)

Intervention Type: DRUG

Oral Corticosteroid (prednisone/prednisolone)

Interventions

Mepolizumab

Mepolizumab is a fully humanised Immunoglobulin G antibody (IgG1, kappa) with human heavy and light chain frameworks.

Intervention Type: DRUG

Placebo

Will be available as an equivalent volume of 0.9% sodium chloride.

Intervention Type: DRUG

OCS (prednisone/prednisolone)

Oral Corticosteroid (prednisone/prednisolone)

Intervention Type: DRUG

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.

• 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

Long Beach, California, United States

GSK Investigational Site

Denver, Colorado, United States

GSK Investigational Site

New Haven, Connecticut, United States

GSK Investigational Site

Rochester, Minnesota, United States

GSK Investigational Site

St Louis, Missouri, United States

GSK Investigational Site

Cincinnati, Ohio, United States

GSK Investigational Site

Pittsburgh, Pennsylvania, United States

GSK Investigational Site

Spartanburg, South Carolina, United States

GSK Investigational Site

New Lambton, New South Wales, Australia

GSK Investigational Site

Bedford Park, South Australia, Australia

GSK Investigational Site

Parkville, Victoria, Australia

GSK Investigational Site

Nedlands, Western Australia, Australia

GSK Investigational Site

Hamilton, Ontario, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Québec, Quebec, Canada

GSK Investigational Site

Brno, , Czechia

GSK Investigational Site

Olomouc, , Czechia

GSK Investigational Site

Prague, , Czechia

GSK Investigational Site

Prague, , Czechia

GSK Investigational Site

Gières, , France

GSK Investigational Site

Montpellier, , France

GSK Investigational Site

Nantes, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Strasbourg, , 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

Gelnhausen, Hesse, Germany

GSK Investigational Site

Neu-Isenburg, Hesse, Germany

GSK Investigational Site

Hanover, Lower Saxony, Germany

GSK Investigational Site

Mainz, Rhineland-Palatinate, Germany

GSK Investigational Site

Lübeck, Schleswig-Holstein, Germany

GSK Investigational Site

Guadalajara, Jalisco, Mexico

GSK Investigational Site

Zapopan, Jalisco, Mexico

GSK Investigational Site

Amsterdam, , Netherlands

GSK Investigational Site

Leeuwarden, , Netherlands

GSK Investigational Site

Rotterdam, , Netherlands

GSK Investigational Site

Bialystok, , Poland

GSK Investigational Site

Bialystok, , Poland

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Lodz, , Poland

GSK Investigational Site

Leicester, Leicestershire, United Kingdom

GSK Investigational Site

Liverpool, , United Kingdom

GSK Investigational Site

Newcastle upon Tyne, , United Kingdom

GSK Investigational Site

Southampton, , United Kingdom

Countries

United States; Australia; Canada; Czechia; France; Germany; Mexico; Netherlands; Poland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35972211 (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)

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)

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.

Reference Type: DERIVED

PMID: 30370691 (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)

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.

Reference Type: DERIVED

PMID: 25199060 (View on PubMed)

Study Documents

Document Type: Study Protocol

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

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Document Type: Dataset Specification

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

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Document Type: Statistical Analysis Plan

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

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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: Clinical Study Report

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: Individual Participant Data Set

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

View Document

Related Links

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Other Identifiers

115575

Identifier Type: -

Identifier Source: org_study_id