Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02020889
Recruitment Status : Completed
First Posted : December 25, 2013
Results First Posted : January 26, 2018
Last Update Posted : January 31, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE December 19, 2013
First Posted Date  ICMJE December 25, 2013
Results First Submitted Date  ICMJE August 29, 2017
Results First Posted Date  ICMJE January 26, 2018
Last Update Posted Date January 31, 2018
Actual Study Start Date  ICMJE February 5, 2014
Actual Primary Completion Date September 5, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2018)
  • Number of Participants in Each Category of Accrued Duration of Remission [ Time Frame: Up to Week 52 ]
    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.
  • Number of Participants Who Are in Remission at 36 and 48 Weeks [ Time Frame: Week 36 and Week 48 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 19, 2013)
  • Total accrued duration of remission [ Time Frame: From Baseline to Week 52 ]
    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 ]
    Remission is defined as BVAS=0 and prednisolone/prednisone dose <=4 mg/day
Change History Complete list of historical versions of study NCT02020889 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 25, 2018)
  • Time to First EGPA Relapse [ Time Frame: Up to Week 52 ]
    EGPA relapse was defined as worsening or persistence of active disease since the last visit characterized by active vasculitis or active asthma symptoms and/or signs with a corresponding worsening in Asthma Control Questionnaire-6 (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: i) an increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalization related to EGPA worsening. Participants who completed study, or withdrawn prematurely from the study without experiencing the event were censored. The number of participants with at least one EGPA relapse during the planned study treatment period are presented.
  • Number of Participants in Each Category of Average Daily Prednisolone/Prednisone Dose During the Last 4 Weeks of the Study Treatment Period. [ Time Frame: Week 48 and Week52 ]
    The number of participants with an average daily prednisolone/prednisone dose during the last 4 weeks of the Study Treatment Period (48 through 52) was calculated. The average dose was categorized into zero, >0 to <=4.0mg, >4.0 to <=7.5mg and >7.5mg. The statistical analysis was performed using a proportional odds regression model with Baseline covariates of treatment group, Baseline prednisolone/prednisone daily dose, Baseline BVAS score and region and the comparison between treatment groups was presented as an odds ratio, p-value and 95 percent CI.
  • Number of Participants Who Achieved Remission Within the First 24 Weeks and Remained in Remission for the Remainder of the Treatment Period [ Time Frame: Up to Week 52 ]
    The number of participants who achieved remission (i.e., BVAS=0 and prednisolone/prednisone<=4 mg/day) within the first 24 weeks and remain in remission for the remainder 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.
  • Number of Participants in Each Category of Accrued Duration of Remission [ Time Frame: Up to Week 52 ]
    Total accrued duration of remission, i.e., the accrued number of weeks where Birmingham Vasculitis Activity Score (BVAS) =0 plus prednisolone/prednisone dose <=7.5mg/day over the 52 week study treatment period was reported. BVAS is a validated, clinician-completed tool used for the comprehensive multisystem clinical assessment of disease activity in systemic vasculitis. The duration was categorized into zero, >0 to <12 weeks, 12 to <24 weeks, 24 to <36 weeks and >=36 weeks. Statistical analysis was performed on ITT Population and was based on a proportional odds regression model with covariates including treatment group, Baseline prednisolone/prednisone daily dose, Baseline BVAS score and region. The odds ratio for treatment difference and associated p-value and 95 percent CI were calculated.
  • Number of Participants Who Are in Remission at 36 and 48 Weeks [ Time Frame: Week 36 and Week 48 ]
    The number of participants who were in remission (i.e ., BVAS=0 and prednisolone /prednisone <=7.5mg/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.
  • Number of Participants Who Achieved Remission (BVAS=0 and Prednisolone/Prednisone <=7.5 mg/Day) Within the First 24 Weeks and Remained in Remission for the Remainder of the Treatment Period [ Time Frame: Up to Week 52 ]
    The number of participants who were in remission (i.e ., BVAS=0 and prednisolone /prednisone <=7.5mg/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.
  • Number of Participants With Local and Systemic Adverse Events (AEs) [ Time Frame: Up to Week 52 ]
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs including systemic allergic and non-allergic reactions as well as local site injection-related reactions were counted throughout treatment phase and follow up phase. Systemic allergic reactions included Facial paralysis, flushing, hypersensitivity and rash pruritic. Injection related reactions were considered as systemic non-allergic reactions. Local site reactions included injection site bruising, erythema, pain and reaction. The analysis was performed on Safety Population which comprised of all participants who receive at least one dose of study treatment.
  • Change From Baseline in Clinical Chemistry Parameters of Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk.Phosph.), Aspartate Aminotransferase (AST), Creatinine Kinase, Gamma Glutamyl Transaminase (GGT) and Lactate Dehydrogenase (Dehydro) Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in ALT, Alk.phosph., AST, creatinine kinase, GGT and lactate dehydro values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Clinical Chemistry Parameters of Albumin and Protein Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in albumin and protein levels values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Clinical Chemistry Parameters of Direct, Indirect and Total Bilirubin and Creatinine Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in direct, indirect and total bilirubin and creatinine values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Calcium, Chloride, Cholesterol, Glucose, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, Phosphorus, Potassium, Sodium, Urea Nitrogen and Very Low Density Lipoprotein (VLDL) Cholesterol Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in calcium, chloride, cholesterol, glucose, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, phosphorus, potassium, sodium, urea nitrogen and very low density lipoprotein (VLDL) cholesterol values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured. NA indicates that data were not available.
  • Change From Baseline in Clinical Chemistry Parameter of Troponin Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in troponin values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Hematology Parameters of Basophils, Eosinophil, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelet values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin Concentration (MCHC) and Hemoglobin Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in MCHC and hemoglobin values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Hematology Parameters of Mean Corpuscle Volume (MCV) Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in MCV values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin (MCH) Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in MCH values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Hematology Parameters of Erythrocytes Levels [ Time Frame: Baseline and up to Week 60 ]
    Blood samples were collected to evaluate change from Baseline in erythrocytes values at Baseline throughout the 52 weeks study treatment and 8-weeks follow up period. Baseline values were taken at Visit 2 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Number of Participants With Anti-Mepolizumab Antibodies [ Time Frame: Up to Week 60 ]
    Blood samples were collected for the determination of anti-Mepolizumab antibodies. Participants who showed presence of anti-Mepolizumab antibody were termed as 'positive' and those who did not have anti-Mepolizumab antibody in blood sample were termed as 'negative'. Participants who did not have a positive ADA assay prior to the first dose of investigational product were included in the analysis.
  • Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Levels [ Time Frame: Baseline up to Week 60 ]
    SBP and DBP were measured from Baseline throughout follow-up (till Week 60) before injection with the participant sitting, having rested in this position for at least 5 minutes before reading. The Baseline value was taken at Visit 2 and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Pulse Rate [ Time Frame: Baseline and up to Week 60 ]
    Pulse rate was measured from Baseline throughout follow-up (till Week 60) before injection with the participant sitting, having rested in this position for at least 5 minutes before reading. The Baseline value was taken at Visit 2 and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Change From Baseline in Body Temperature [ Time Frame: Baseline and up to Week 60 ]
    Body temperature was measured from Baseline throughout follow-up (till Week 60). The Baseline value was taken at Visit 2 and change from Baseline was defined as post dose visit value minus Baseline value. The analysis was performed on Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were measured.
  • Mean Change From Baseline in QT Interval Corrected by Fridericia's Method (QTcF) and QT Interval Corrected by Bazett's Method (QTcB) Values [ Time Frame: Baseline and up to Week 60 ]
    Single measurements of 12-lead electrocardiogram (ECGs) were obtained after 5 minutes rest in a supine position at Baseline throughout the 52 weeks treatment period and 8 weeks follow-up period using an ECG machine. Mean change from Baseline in QTcF and QTcB values were measured. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
  • Maximum Change From Baseline in QTcF and QTcB Values [ Time Frame: Baseline and up to Week 60 ]
    Single measurements of 12-lead ECGs were obtained after 5 minutes rest in a supine position at Baseline throughout the 52 weeks treatment period and 8 weeks follow-up period using an ECG machine. Maximum change from Baseline in QTcF and QTcB values were measured.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2013)
  • Time to first confirmed EGPA relapse [ Time Frame: Baseline to Week 52 ]
    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 ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Investigate Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Churg-Strauss Syndrome
Intervention  ICMJE
  • 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.
  • Drug: Placebo
    Placebo will be available as 0.9% sodium chloride
Study Arms  ICMJE
  • 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.
    Intervention: Biological: Mepolizumab
  • 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.
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2016)
136
Original Estimated Enrollment  ICMJE
 (submitted: December 19, 2013)
130
Actual Study Completion Date  ICMJE September 5, 2016
Actual Primary Completion Date September 5, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Germany,   Italy,   Japan,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02020889
Other Study ID Numbers  ICMJE 115921
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP