Clinical trial NCT02020889: A Study to Investigate Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Churg-Strauss Syndrome
Keywords: eosinophils
SB 240563
Churg-Strauss Syndrome
quality of life
mepolizumab
safety
biomarkers
efficacy
corticosteroids
Eosinophilic granulomatosis with polyangiitis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2013-12-25
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Number of Participants in Each Category of Accrued Duration of Remission
timeFrame: Up to Week 52
measure: Number of Participants Who Are in Remission at 36 and 48 Weeks
timeFrame: Week 36 and Week 48
Secondary outcomes:
measure: Time to First EGPA Relapse
timeFrame: Up to Week 52
measure: Number of Participants in Each Category of Average Daily Prednisolone/Prednisone Dose During the Last 4 Weeks of the Study Treatment Period.
timeFrame: Week 48 and Week52
measure: Number of Participants Who Achieved Remission Within the First 24 Weeks and Remained in Remission for the Remainder of the Treatment Period
timeFrame: Up to Week 52
measure: Number of Participants in Each Category of Accrued Duration of Remission
timeFrame: Up to Week 52
measure: Number of Participants Who Are in Remission at 36 and 48 Weeks
timeFrame: Week 36 and Week 48
measure: 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
timeFrame: Up to Week 52
measure: Number of Participants With Local and Systemic Adverse Events (AEs)
timeFrame: Up to Week 52
measure: 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
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Clinical Chemistry Parameters of Albumin and Protein Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Clinical Chemistry Parameters of Direct, Indirect and Total Bilirubin and Creatinine Levels
timeFrame: Baseline and up to Week 60
measure: 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
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Clinical Chemistry Parameter of Troponin Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Hematology Parameters of Basophils, Eosinophil, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin Concentration (MCHC) and Hemoglobin Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Hematology Parameters of Mean Corpuscle Volume (MCV) Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin (MCH) Levels
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Hematology Parameters of Erythrocytes Levels
timeFrame: Baseline and up to Week 60
measure: Number of Participants With Anti-Mepolizumab Antibodies
timeFrame: Up to Week 60
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Levels
timeFrame: Baseline up to Week 60
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline and up to Week 60
measure: Change From Baseline in Body Temperature
timeFrame: Baseline and up to Week 60
measure: Mean Change From Baseline in QT Interval Corrected by Fridericia's Method (QTcF) and QT Interval Corrected by Bazett's Method (QTcB) Values
timeFrame: Baseline and up to Week 60
measure: Maximum Change From Baseline in QTcF and QTcB Values
timeFrame: Baseline and up to Week 60
Other outcomes:
Locations:
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Bethesda
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Bron Cedex
country: France
facility: GSK Investigational Site
city: Marseille cedex 20
country: France
facility: GSK Investigational Site
city: Montpellier cedex 5
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Suresnes
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Fulda
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Bad Bramstedt
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Jena
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Kirchheim unter Teck
country: Germany
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
city: Portsmouth
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.