A Study to Investigate Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis

NCT02020889 | Completed Phase 3 Results DMC

• 1 other identifier: 115921
• Study Type: interventional
• Target: 136
• Locations: 9 countries
• Sites: 32

Brief Summary

The purpose of this randomized, double-blind study is to investigate the efficacy and safety of mepolizumab (300 milligram \[mg\] administered subcutaneously \[SC\] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA) receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. During the treatment period, in accordance with standard of care, corticosteroid dose will be tapered. The key outcomes in the study focus on evaluation of clinical remission, defined as Birmingham Vasculitis Activity Score (BVAS)=0 with a corticosteroid dose of \<=4 mg/day prednisolone/prednisone, reduction in disease relapse and reduction in corticosteroid requirement.

Conditions

Churg-Strauss Syndrome

Keywords

eosinophils; SB 240563; Churg-Strauss Syndrome; quality of life; mepolizumab; safety; biomarkers; efficacy; corticosteroids; Eosinophilic granulomatosis with polyangiitis

Outcome Measures

Primary Outcomes (2)

• Number of Participants in Each Category of Accrued Duration of Remission

  Total accrued duration of remission is the accrued number of weeks where Birmingham Vasculitis Activity Score (BVAS) =0 plus prednisolone/prednisone dose \<=4 mg/day over the 52 week study treatment period was reported. The accrued duration was categorized into zero, \>0 to \<12 weeks, 12 to \<24 weeks, 24 to \<36 weeks and \>=36 weeks. Statistical analysis was based on a proportional odds regression model with covariates including treatment group, Baseline prednisolone/prednisone daily dose, Baseline BVAS score and region. Intent-to-Treat (ITT) Population was used for the analysis and was defined as all participants who were randomized and received at least one dose of trial medication. Randomized participants were assumed to have received study treatment unless definitive evidence to the contrary exists. The odds ratio for treatment difference and associated probability (p)-value and 95 percent confidence interval (CI) were calculated.

  Up to Week 52

• Number of Participants Who Are in Remission at 36 and 48 Weeks

  The number of participants who were in remission (i.e ., BVAS=0 and prednisolone /prednisone \<=4 mg/day) at both Weeks 36 and 48 of the study treatment period was reported. The statistical analysis was performed using a logistic regression model on ITT Population. The odds ratio for treatment difference and associated p-value and 95 percent CI were calculated.

  Week 36 and Week 48

Secondary Outcomes (23)

• Time to First EGPA Relapse

  Up to Week 52

• Number of Participants in Each Category of Average Daily Prednisolone/Prednisone Dose During the Last 4 Weeks of the Study Treatment Period.

  Week 48 and Week52

• Number of Participants Who Achieved Remission Within the First 24 Weeks and Remained in Remission for the Remainder of the Treatment Period

  Up to Week 52

• Number of Participants in Each Category of Accrued Duration of Remission

  Up to Week 52

• Number of Participants Who Are in Remission at 36 and 48 Weeks

  Week 36 and Week 48

Study Arms (2)

Mepolizumab 300 mg

EXPERIMENTAL

Each subject will receive mepolizumab 300 mg subcutaneous (SC) injection every 4 weeks (13 administrations) along with standard care. It will be administered as 3 separate injections (100 mg each- total dose 300 mg); individual injection sites will be separated by at least 5 cm. It will be administered into any of the upper arm, thigh or anterior abdominal wall.

Biological: Mepolizumab

Placebo

PLACEBO COMPARATOR

Each subject will receive placebo (0.9% sodium chloride) SC injection every 4 weeks (13 administrations) along with standard care. It will be administered as 3 separate injections; individual injection sites will be separated by at least 5 cm. It will be administered into any of the upper arm, thigh or anterior abdominal wall.

Drug: Placebo

Interventions

Mepolizumab BIOLOGICAL

Mepolizumab will be provided as a lyophilized cake in sterile vials for individual use to be reconstituted with sterile water for Injection, just prior to use.

Mepolizumab 300 mg

Placebo DRUG

Placebo will be available as 0.9% sodium chloride

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed Consent: 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. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
• Age and gender: Male or female subjects age 18 years or older.
• EGPA diagnosis: subjects who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia (\>1.0x10\^9/Liter and/or \>10% of leucocytes) plus at least two of the following additional features of EGPA; a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation; neuropathy, mono or poly (motor deficit or nerve conduction abnormality); pulmonary infiltrates, non-fixed; sino-nasal abnormality; cardiomyopathy (established by echocardiography or Magnetic Resonance Imaging); glomerulonephritis (haematuria, red cell casts, proteinuria); alveolar haemorrhage (by bronchoalveolar lavage); palpable purpura; anti neutrophil cytoplasmic anti-body (ANCA) positive (Myeloperoxidase or proteinease 3).
• History of relapsing OR refractory disease defined as: Relapsing disease:
• Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in oral corticosteroids (OCS) dose, initiation/increased dose of immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of \>=7.5 milligram per day (mg/day). Refractory disease: Either: Failure to attain remission (BVAS=0 and OCS dose \<=7.5 mg/day prednisolone or equivalent) within the last 6 months following induction treatment with a standard regimen, administered for at least 3 months. Note: a) Subjects who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed intravenous CYC prior to Baseline (Visit 2), if their total white blood cells (WBC) is \>=4x10\^9/Liter (tested at the local laboratory, if necessary) prior to randomisation. b) Subjects who have received a methotrexate, azathioprine, or mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to Baseline (Visit 2). c) Subjects who have received an induction regimen comprising corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment AND the corticosteroid dose is \>=15 mg/day prednisolone or equivalent for the 4 weeks prior to Baseline (Visit 2). Or: Within 6 months prior to Screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) whilst tapering OCS, occurring at any dose level \>=7.5 mg/day prednisolone or equivalent.
• Corticosteroid therapy: Subject must be on a stable dose of oral prednisolone or prednisone of \>=7.5 mg/day (but not \>50 mg/day) for at least 4 weeks prior to Baseline (Visit 2).
• Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding cyclophosphamide) the dosage must be stable for the 4 weeks prior to Baseline (Visit 2) and during the study (dose reductions for safety reasons will be permitted).
• ECG measurements: QTc(F)\<450 msec or QTc(F)\<480 msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal decisions, QTcFwill be used. For purposes of data analysis, QTcF will be used as primary though data using both correction formulas will be collected and analysed. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.
• Female subjects: To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control (as discussed in the protocol) beginning with consent, for the duration of the trial and for 4 months after the last study drug administration.
• Liver Function Tests: obtained at Screening (Visit 1): ALT\<2x ULN (upper limit of normal) or if subject is on background methotrexate or azathioprine \<3x ULN; AST\<2x ULN or if subject is on background methotrexate or azathioprine \<3x ULN; Alkaline Phosphatase ≤2.0x ULN;Bilirubin ≤ 1.5x ULN (isolated bilirubin\>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)

You may not qualify if:

• GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener's granulomatosis) or microscopic polyangiitis (MPA).
• Organ-threatening EGPA: Organ-threatening EGPA as per European league against rheumatism (EULAR) criteria, i.e., organ failure due to active vasculitis, creatinine \>5.8 gram per deciliter (g/dL) (\>513 micromole per liter \[µmol/L\]) within 3 months prior to Screening (Visit 1).
• Life-threatening EGPA: Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1); Intensive care required; Severe alveolar haemorrhage or haemoptysis requiring transfusion or ventilation or haemoglobin \< 8 gram per liter (g/dL) (\<80 g/L) or drop in haemoglobin \> 2 g/dL (\>20 g/L) over a 48 hour period due to alveolar haemorrhage; Rapidly progressive glomerulonephritis (RPGN) with creatinine \> 2.5 milligram per deciliter (mg/dL) (\>221 µmol/L) or rise in creatinine \> 2 mg/dL (\>177 µmol/L) over a 48 hour period; Severe gastrointestinal (GI) involvement, e.g., gangrene, bleeding requiring surgery; Severe central nervous system (CNS) involvement; Severe cardiac involvement, e.g., life-threatening arrhythmia, cardiac failure: ejection fraction \< 20%, New York Heart Association Class III/IV (as discussed in protocol), acute myocardial infarction.
• Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded).
• Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to: Known ejection fraction of \<30%, OR Severe heart failure that meets New York Heart Association Class IV (as discussed in protocol), OR Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (as discussed in protocol), OR Angina diagnosed less than 3 months prior to or at Visit 1 (Screening).
• Other concurrent medical conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.
• Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.
• Parasitic infection: Subjects with a parasitic infestation within 6 months prior to Screening (Visit 1).
• Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1). Japan only: Subjects positive for HBsAg , antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1). Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.
• HIV: Subjects with a known human immunodeficiency virus infection.
• Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic therapy.
• Previous mepolizumab: Subjects who have previously received mepolizumab within a 1 year period prior to Screening (Visit 1).
• Prohibited medications: Subjects receiving any of the following: OCS: Subject requires an oral corticosteroid dose of \>50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2); Intravenous or SC corticosteroids in the 4-week period prior to Baseline (Visit 2); Omalizumab within 130 days prior to Screening (Visit 1); Cyclophosphamide: oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is \>=4x10\^9/Liter (measured using the local laboratory if necessary); Rituximab within 12 months prior to Screening (Visit 1); in addition, the subject must have shown recovery of peripheral B-cell count to within the normal range; IV or SC immunoglobulin within 6 months prior to Screening (Visit 1); Interferon-α within 6 months prior to Screening (Visit 1); Anti-TNF therapy within 12 weeks prior to Screening (Visit 1); Anti-CD52 (alemtuzumab) within 6 months prior to Screening (Visit 1).
• Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (32)

GSK Investigational Site

Denver, Colorado, 80206, United States

Location

GSK Investigational Site

Bethesda, Maryland, 20892, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02118-2307, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

GSK Investigational Site

Cleveland, Ohio, 44195, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84132, United States

Location

GSK Investigational Site

Brussels, 1070, Belgium

Location

GSK Investigational Site

Hamilton, Ontario, L8N 4A6, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5T 3L9, Canada

Location

GSK Investigational Site

Bron, 69677, France

Location

GSK Investigational Site

Marseille, 13915, France

Location

GSK Investigational Site

Montpellier, 34295, France

Location

GSK Investigational Site

Paris, 75014, France

Location

GSK Investigational Site

Suresnes, 92151, France

Location

GSK Investigational Site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

GSK Investigational Site

Fulda, Hesse, 36043, Germany

Location

GSK Investigational Site

Bad Bramstedt, Schleswig-Holstein, 24576, Germany

Location

GSK Investigational Site

Jena, Thuringia, 07740, Germany

Location

GSK Investigational Site

Hamburg, 22767, Germany

Location

GSK Investigational Site

Kirchheim unter Teck, 73230, Germany

Location

GSK Investigational Site

Milan, Lombardy, 20132, Italy

Location

GSK Investigational Site

Milan, Lombardy, 20162, Italy

Location

GSK Investigational Site

Florence, Tuscany, 50134, Italy

Location

GSK Investigational Site

Pisa, Tuscany, 56126, Italy

Location

GSK Investigational Site

Kanagawa, 252-0392, Japan

Location

GSK Investigational Site

Miyagi, 980-8574, Japan

Location

GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

Cambridge, CB2 2QQ, United Kingdom

Location

GSK Investigational Site

Leicester, LE3 9QP, United Kingdom

Location

GSK Investigational Site

Portsmouth, PO6 3LY, United Kingdom

Location

Related Publications (1)

• Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, Merkel PA, Moosig F, Specks U, Cid MC, Luqmani R, Brown J, Mallett S, Philipson R, Yancey SW, Steinfeld J, Weller PF, Gleich GJ; EGPA Mepolizumab Study Team. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017 May 18;376(20):1921-1932. doi: 10.1056/NEJMoa1702079.

  PMID: 28514601 DERIVED

MeSH Terms

Conditions

Churg-Strauss Syndrome

Interventions

mepolizumab

Condition Hierarchy (Ancestors)

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Granuloma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2013
• First Posted: December 25, 2013
• Study Start: February 5, 2014
• Primary Completion: September 5, 2016
• Study Completion: September 5, 2016
• Last Updated: January 31, 2018
• Results First Posted: January 26, 2018

Record last verified: 2018-01

Locations

DE (6); GB (3); US (8); BE (1); IT (4); CA (2); ES (1); FR (5); JP (2)