A Study to Investigate Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis
Condition: Churg-Strauss Syndrome
MeSH terms: Granulomatosis with Polyangiitis; Systemic Vasculitis; Churg-Strauss Syndrome
Intervention: Mepolizumab; Placebo
Intervention description: 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 will be available as 0.9% sodium chloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 136.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: eosinophils; SB 240563; Churg-Strauss Syndrome; quality of life; mepolizumab; safety; biomarkers; efficacy; corticosteroids; Eosinophilic granulomatosis with polyangiitis

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.
    

Eligibility 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.

          -  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%)

        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).

          -  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).