Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES)

NCT ID: NCT02836496

Last Updated: 2020-02-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-07
• Study Completion Date: 2019-08-08

Brief Summary

Mepolizumab is a humanized monoclonal antibody. In conditions where eosinophilia is considered to play an important part in the pathology, including eosinophilic asthma, HES, and eosinophilic granulomatosis with polyangiitis, a consistent reduction in blood eosinophil counts is observed in association with mepolizumab administration, with concomitant clinical improvement. This is a 32-week treatment period, randomized, double-blind, placebo-controlled, parallel group, multicentre study of mepolizumab in adolescent and adult subjects with severe HES receiving standard of care (SoC) therapy. This study will demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control of HES symptoms during the treatment period. The study will comprise of a screening period of up to approximately 4 weeks followed by a 32-Week study treatment period (subjects will be randomized 1:1 to placebo or mepolizumab) and up to 8-week additional follow-up period (12 weeks after the last dose of study treatment).

Conditions

Hypereosinophilic Syndrome

Study Design

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

Study Groups

Mepolizumab

Enrolled subjects will receive either mepolizumab 300 mg or placebo subcutaneous (SC) every 4 weeks while continuing their HES therapy.

Group Type: EXPERIMENTAL

Mepolizumab 300 mg

Intervention Type: DRUG

Mepolizumab is available as lyophilized powder for injection reconstituted with Sterile Water for Injection, just prior to use.

Active OCS capsules (5 mg prednisolone or prednisone)

Intervention Type: DRUG

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed. Subjects with an increase in blood eosinophils above the pre-specified threshold will be instructed to start blinded OCS treatment from one of the bottles provided (active treatment) unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Placebo matching OCS capsules

Intervention Type: DRUG

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed.A subject who does not reach the pre-specified blood eosinophil threshold with a similar blood draw date will be selected to initiate a placebo OCS treatment in a blinded manner, unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Placebo

Enrolled subjects will receive either mepolizumab 300 mg or placebo SC every 4 weeks while continuing their HES therapy.

Group Type: PLACEBO_COMPARATOR

Placebo matching mepolizumab

Intervention Type: DRUG

Placebo is available as 0.9% sodium chloride solution

Active OCS capsules (5 mg prednisolone or prednisone)

Intervention Type: DRUG

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed. Subjects with an increase in blood eosinophils above the pre-specified threshold will be instructed to start blinded OCS treatment from one of the bottles provided (active treatment) unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Placebo matching OCS capsules

Intervention Type: DRUG

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed.A subject who does not reach the pre-specified blood eosinophil threshold with a similar blood draw date will be selected to initiate a placebo OCS treatment in a blinded manner, unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Interventions

Mepolizumab 300 mg

Mepolizumab is available as lyophilized powder for injection reconstituted with Sterile Water for Injection, just prior to use.

Intervention Type: DRUG

Placebo matching mepolizumab

Placebo is available as 0.9% sodium chloride solution

Intervention Type: DRUG

Active OCS capsules (5 mg prednisolone or prednisone)

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed. Subjects with an increase in blood eosinophils above the pre-specified threshold will be instructed to start blinded OCS treatment from one of the bottles provided (active treatment) unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Intervention Type: DRUG

Placebo matching OCS capsules

All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed.A subject who does not reach the pre-specified blood eosinophil threshold with a similar blood draw date will be selected to initiate a placebo OCS treatment in a blinded manner, unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol
• Twelve years of age or older, at the time of signing the informed consent/assent
• Subjects who have been diagnosed with HES for at least 6 months at randomization
• A history of two or more HES flares within the past 12 months prior to screening. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy. At least one HES flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
• Subjects must have blood eosinophil count >=1000 cells/µL present in the sample collected during screening (within 4 weeks prior to randomization).
• Subjects must be on a stable dose of HES therapy for the 4 weeks prior to randomization. HES therapy includes but is not limited to oral corticosteroid, immunosuppressive, and cytotoxic therapy.
• Male or female. A female subject is eligible to participate if she is not pregnant, not lactating, and either non-reproductive potential or reproductive potential and agree to use a highly effective method to avoid pregnancy from 30 days prior to the first dose of study medication and until 4 months after the last dose of study treatment.

Exclusion Criteria

• Life-threatening HES or life-threatening HES co-morbidities: Imminently life-threatening HES disease severity such that the likelihood of death is high unless the course of the disease is interrupted within 12 weeks prior to randomization.
• Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological, respiratory or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.
• Eosinophilia of unknown clinical significance
• Twelve-lead electrocardiogram (ECG) finding: QT interval corrected for heart rate (QTc) > 450 msec or QTc > 480 msec in subjects with bundle branch block or an abnormal ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant and would impact the subject's participation during the study based on the evaluation of the Investigator.
• Subjects with documented history of any clinically significant cardiac damage prior to screening that, in the opinion of the investigator, would impact the subject's participation during the study.
• Liver abnormality/disease - Alanine transaminase (ALT) >2.5x upper limit of normal (ULN) or ALT>5xULN if documented HES with liver manifestations, or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent), or current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.

NOTE: Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.

• Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)
• Subjects with a history of or current lymphoma, or subjects with current malignancy or previous history of cancer in remission for less than 12 months prior to randomization. Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded.
• FIP1 like 1-platelet derived growth factor receptor (FIP1L1-PDGFR) Status: Subjects who test positive for the FIP1L1-PDGFR fusion tyrosine kinase gene translocation.
• Subjects with chronic or ongoing active infections requiring systemic treatment, as well as subjects who have experienced clinically significant infections due to viruses, bacteria, and fungi within 4 weeks prior to randomization or subjects with a pre-existing helminthes infestation within 6 months prior to randomization
• Subjects with a known human immunodeficiency virus (e.g., HIV), other than that explained by the use of OCS or other therapy taken for HES.
• Other laboratory abnormalities: Evidence of clinically significant abnormality in the hematological, biochemical or urinalysis screen from the sample collected at screening, that could put the subject's safety at risk by participating in the study, as judged by the investigator
• Subjects who have previously received mepolizumab in the 4 months prior to randomization
• Subjects receiving intravenous or subcutaneous corticosteroids in the 4-week period prior to randomization or any other monoclonal antibodies within 30 days or 5 half-lives, whichever is longer, of randomization
• Subjects who have received treatment with an investigational agent (biologic or non-biologic) within the past 30 days or 5 drug half-lives whichever is longer, prior to randomization or subjects who are currently participating in any other interventional clinical study
• Subjects who are not responsive to oral corticosteroid based on clinical response or blood eosinophil counts
• Subjects with any history of hypersensitivity to any monoclonal antibody (including mepolizumab) or any steroid or steroid-containing product
• Subjects with a known or suspected history of alcohol or substance abuse at screening which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirement.

• 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

San Diego, California, United States

GSK Investigational Site

New Haven, Connecticut, United States

GSK Investigational Site

Rochester, Minnesota, United States

GSK Investigational Site

Cincinnati, Ohio, United States

GSK Investigational Site

Mayfield Heights, Ohio, United States

GSK Investigational Site

Charleston, South Carolina, United States

GSK Investigational Site

Salt Lake City, Utah, United States

GSK Investigational Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

La Plata, Buenos Aires, Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Brussels, , Belgium

GSK Investigational Site

Leuven, , Belgium

GSK Investigational Site

Porto Alegre, Rio Grande do Sul, Brazil

GSK Investigational Site

Blumenau, Santa Catarina, Brazil

GSK Investigational Site

Santo André - SP, São Paulo, Brazil

GSK Investigational Site

Sorocaba, São Paulo, Brazil

GSK Investigational Site

Lille, , France

GSK Investigational Site

Nantes, , France

GSK Investigational Site

Suresnes, , France

GSK Investigational Site

Toulouse, , France

GSK Investigational Site

Kirchheim -Teck, Baden-Wurttemberg, Germany

GSK Investigational Site

Mannheim, Baden-Wurttemberg, Germany

GSK Investigational Site

Munich, Bavaria, Germany

GSK Investigational Site

Fulda, Hesse, Germany

GSK Investigational Site

Hanover, Lower Saxony, Germany

GSK Investigational Site

Napoli, Campania, Italy

GSK Investigational Site

Florence, Tuscany, Italy

GSK Investigational Site

Guadalajara, Jalisco, Mexico

GSK Investigational Site

Monterrey, Nuevo León, Mexico

GSK Investigational Site

Villahermosa, Tabasco, Mexico

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Lodz, , Poland

GSK Investigational Site

Bucharest, , Romania

GSK Investigational Site

Cluj-Napoca, , Romania

GSK Investigational Site

Târgu Mureş, , Romania

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Valencia, , Spain

GSK Investigational Site

Leicester, , United Kingdom

Countries

United States; Argentina; Belgium; Brazil; France; Germany; Italy; Mexico; Poland; Romania; Russia; Spain; United Kingdom

References

Roufosse F, Butterfield J, Steinfeld J, Bentley JH, von Maltzahn R, Kwon N, Nelsen L. Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome. Front Med (Lausanne). 2023 Mar 29;10:1035250. doi: 10.3389/fmed.2023.1035250. eCollection 2023.

Reference Type: DERIVED

PMID: 37064032 (View on PubMed)

Pane F, Lefevre G, Kwon N, Bentley JH, Yancey SW, Steinfeld J. Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome. Front Immunol. 2022 Aug 26;13:935996. doi: 10.3389/fimmu.2022.935996. eCollection 2022.

Reference Type: DERIVED

PMID: 36091012 (View on PubMed)

Rothenberg ME, Roufosse F, Faguer S, Gleich GJ, Steinfeld J, Yancey SW, Mavropoulou E, Kwon N; HES Mepolizumab Study Group. Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5. J Allergy Clin Immunol Pract. 2022 Sep;10(9):2367-2374.e3. doi: 10.1016/j.jaip.2022.04.037. Epub 2022 May 12.

Reference Type: DERIVED

PMID: 35568330 (View on PubMed)

Reiter A, Lefevre G, Cid MC, Kwon N, Mavropolou E, Yancey SW, Steinfeld J. Association Between Baseline Therapy and Flare Reduction in Mepolizumab-Treated Patients With Hypereosinophilic Syndrome. Front Immunol. 2022 Apr 13;13:840974. doi: 10.3389/fimmu.2022.840974. eCollection 2022.

Reference Type: DERIVED

PMID: 35493455 (View on PubMed)

Gleich GJ, Roufosse F, Chupp G, Faguer S, Walz B, Reiter A, Yancey SW, Bentley JH, Steinfeld J; HES Mepolizumab Study Group. Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study. J Allergy Clin Immunol Pract. 2021 Dec;9(12):4431-4440.e1. doi: 10.1016/j.jaip.2021.07.050. Epub 2021 Aug 10.

Reference Type: DERIVED

PMID: 34389506 (View on PubMed)

Roufosse F, Kahn JE, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, Gilson MJ, Bentley JH, Bradford ES, Yancey SW, Steinfeld J, Gleich GJ; HES Mepolizumab study group. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020 Dec;146(6):1397-1405. doi: 10.1016/j.jaci.2020.08.037. Epub 2020 Sep 18.

Reference Type: DERIVED

PMID: 32956756 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

200622

Identifier Type: -

Identifier Source: org_study_id