NCT02020889已完成3 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 136
- 试验地点
- 1
- 主要终点
- Number of Participants in Each Category of Accrued Duration of Remission
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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%)
排除标准
- •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).
研究组 & 干预措施
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.
干预措施: Mepolizumab (Biological)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants in Each Category of Accrued Duration of Remission
时间窗: 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
时间窗: 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.
次要结局
- 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 Who Are in Remission at 36 and 48 Weeks(Week 36 and Week 48)
- Change From Baseline in Clinical Chemistry Parameters of Albumin and Protein Levels(Baseline and up to Week 60)
- Change From Baseline in Clinical Chemistry Parameters of Direct, Indirect and Total Bilirubin and Creatinine Levels(Baseline and up to Week 60)
- Change From Baseline in Hematology Parameters of Mean Corpuscle Volume (MCV) Levels(Baseline and up to Week 60)
- Change From Baseline in Hematology Parameters of Erythrocytes Levels(Baseline and up to Week 60)
- Change From Baseline in Body Temperature(Baseline and up to Week 60)
- Mean Change From Baseline in QT Interval Corrected by Fridericia's Method (QTcF) and QT Interval Corrected by Bazett's Method (QTcB) Values(Baseline and up to Week 60)
- Time to First EGPA Relapse(Up to Week 52)
- Number of Participants in Each Category of Accrued Duration of Remission(Up to Week 52)
- Change From Baseline in Pulse Rate(Baseline and up to Week 60)
- Maximum Change From Baseline in QTcF and QTcB Values(Baseline and up to Week 60)
- 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(Up to Week 52)
- Number of Participants With Local and Systemic Adverse Events (AEs)(Up to Week 52)
- Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin Concentration (MCHC) and Hemoglobin Levels(Baseline and up to Week 60)
- Change From Baseline in Hematology Parameters of Mean Corpuscle Hemoglobin (MCH) Levels(Baseline and up to Week 60)
- Number of Participants With Anti-Mepolizumab Antibodies(Up to Week 60)
- 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(Baseline and up to Week 60)
- Change From Baseline in Clinical Chemistry Parameter of Troponin Levels(Baseline and up to Week 60)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Levels(Baseline up to Week 60)
- 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(Baseline and up to Week 60)
- Change From Baseline in Hematology Parameters of Basophils, Eosinophil, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets Levels(Baseline and up to Week 60)
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