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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by GlaxoSmithKline
Sponsor:
Collaborator:
United States: National Institute of Health; National Institute of Allergy and Infectious Diseases (NIAID) division
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT02020889
First received: December 19, 2013
Last updated: September 4, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Churg-Strauss Syndrome
Biological: Mepolizumab
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis in Subjects Receiving Standard of Care Therapy

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Total accrued duration of remission [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    The accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose <=4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories: Zero, >0 to <12 weeks, 12 to <24 weeks, 24 to <36 weeks, >=36 weeks

  • The proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period [ Time Frame: Weeks 36 and 48 ] [ Designated as safety issue: No ]
    Remission is defined as BVAS=0 and prednisolone/prednisone dose <=4 mg/day


Secondary Outcome Measures:
  • Time to first confirmed EGPA relapse [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
    EGPA relapse is defined as worsening or persistence of active disease characterised by active vasculitis (BVAS >0) or active asthma symptoms and/or signs with a corresponding worsening in Asthma Control Questionnaire (ACQ) 6 score or active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions warranting an increased dose of OCS therapy or an increased dose or addition of immunosuppressive therapy or hospitalisation related to EGPA worsening

  • The proportion of subjects with an average daily prednisolone/prednisone dose of 0 mg, >0 to <=4.0 mg, >4.0 to <=7.5 mg and >7.5 mg during the last 4 weeks of the study treatment period (48 through 52) [ Time Frame: Week 48 to Week 52 ] [ Designated as safety issue: No ]
  • The proportion of subjects in each treatment group who achieve remission (BVAS=0 and prednisolone/prednisone dose <=4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]

Estimated Enrollment: 130
Study Start Date: February 2014
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mepolizumab 300 mg
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
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.
Placebo Comparator: Placebo
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
Placebo will be available as 0.9% sodium chloride

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

  • 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).
  • 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%)
  • Other laboratory parameter exclusions: Creatinine > 2.5 mg/dL (221 µmol/L); WBC < 4 x10^9/Liter, Platelet count <120,000/millimetre cube (mm^3), Haemoglobin <8 g/dL (<80 g/L)
  • Pregnancy: Subjects who are pregnant or breastfeeding. Subjects 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 Screening (Visit 1).
  • Other investigational product: Subjects who have received treatment with an investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Screening (Visit 1) (this also includes investigational formulations of marketed products).
  • Other clinical study: Subject is currently participating in any other interventional clinical study.
  • Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
  • French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days or 5 half-lives (whichever is longer).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02020889

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 28 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
United States: National Institute of Health; National Institute of Allergy and Infectious Diseases (NIAID) division
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02020889     History of Changes
Other Study ID Numbers: 115921
Study First Received: December 19, 2013
Last Updated: September 4, 2014
Health Authority: United States: Food and Drug Administration
Italy: Agenzia Italiana del Farmaco
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Belgium: Belgian Federal Agency for Medicinal and Health Products
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte
Japan: Pharmaceuticals and Medical Devices Agency
Spain: Spanish Agency for Medicines and Health Products
Canada: Health Canada
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
eosinophils
SB 240563
Churg-Strauss Syndrome
quality of life
mepolizumab
safety
biomarkers
efficacy
corticosteroids
Eosinophilic granulomatosis with polyangiitis

Additional relevant MeSH terms:
Churg-Strauss Syndrome
Systemic Vasculitis
Syndrome
Wegener Granulomatosis
Vasculitis
Vascular Diseases
Cardiovascular Diseases
Disease
Pathologic Processes
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Autoimmune Diseases
Immune System Diseases
Granuloma
Lymphoproliferative Disorders
Lymphatic Diseases

ClinicalTrials.gov processed this record on September 22, 2014