A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Safety and Efficacy of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 331
- 试验地点
- 1
- 主要终点
- Percentage of Subjects Achieving Sustained Disease Remission at Week 52
研究概览
简要总结
The primary objective is to evaluate the efficacy of CCX168 (avacopan) to induce and sustain remission in patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), when used in combination with cyclophosphamide followed by azathioprine, or in combination with rituximab.
详细描述
Complement 5a and its receptor C5aR (CD88) are involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
This is a randomized, double-blind, active-controlled Phase 3 study to evaluate the safety and efficacy of the orally-administered, selective C5aR inhibitor CCX168 (avacopan) in inducing and sustaining remission in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated concomitantly with Rituximab or Cyclophosphamide/Azathioprine.
Study acquired by Amgen and all disclosures were done by previous sponsor ChemoCentryx.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This study was double-blind, double-dummy, i.e., placebo capsules were identical in appearance to the avacopan capsules, and prednisone capsules also had matching placebo capsules. To maintain the blind, multiple measures were taken (i.e., randomization code was not accessible to study personnel who had contact with study centers or who were involved in data management and analysis for the duration of the study).
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical diagnosis of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis
- •Male and female subjects, aged at least 18 years, with newly-diagnosed or relapsed associated vasculitis (AAV) where treatment with cyclophosphamide or rituximab is needed; where approved by Regulatory Agencies, adolescents (12-17 year old) may be enrolled
- •Use of adequate contraception
- •Positive test for anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO)
- •At least 1 major item, or at least 3 non-major items, or at least the 2 renal items of proteinuria and hematuria on Birmingham Vasculitis Activity Score (BVAS)
- •Estimated glomerular filtration rate ≥15 mL/minute/1.73 m^2 at screening
排除标准
- •Pregnant or breast-feeding
- •Alveolar hemorrhage requiring pulmonary ventilation support at screening
- •Any other known multi-system autoimmune disease
- •Required dialysis or plasma exchange within 12 weeks prior to screening
- •Have a kidney transplant
- •Received cyclophosphamide within 12 weeks prior to screening; if on azathioprine, mycophenolate mofetil or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or rituximab dose on Day 1
- •Received intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening
- •Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to screening
- •Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred (i.e., CD19 count > 0.01x10^9/L); received anti-tumor necrosis factor (TNF) treatment, abatacept, alemtuzumab, intravenous immunoglobulin (IVIg), belimumab, tocilizumab, or eculizumab within 12 weeks prior to screening
- •For patients scheduled to receive cyclophosphamide treatment, urinary outflow obstruction, active infection (especially varicella zoster infection), or platelet count <50,000/μL before start of dosing
- •Participated previously in a CCX168 study
研究组 & 干预措施
Prednisone group
Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
干预措施: Prednisone (Drug)
Prednisone group
Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
干预措施: Cyclophosphamide (Drug)
Prednisone group
Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
干预措施: Rituximab (Biological)
Prednisone group
Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
干预措施: Azathioprine (Drug)
Avacopan group
Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
干预措施: Avacopan (Drug)
Avacopan group
Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
干预措施: Cyclophosphamide (Drug)
Avacopan group
Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
干预措施: Rituximab (Biological)
Avacopan group
Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
干预措施: Azathioprine (Drug)
结局指标
主要结局
Percentage of Subjects Achieving Sustained Disease Remission at Week 52
时间窗: Week 52
Sustained remission at Week 52 was defined as: * Disease remission at Week 26 as defined above; * Disease remission at Week 52 defined as a BVAS of 0 at Week 52 as determined by the Adjudication Committee and no administration of glucocorticoids for treatment of ANCA-associated vasculitis within 4 weeks prior to Week 52; * No disease relapse between Week 26 and Week 52 as determined by the Adjudication Committee.
Percentage of Subjects Achieving Disease Remission at Week 26
时间窗: Week 26
Disease remission at Week 26 was defined as: * Achieving a BVAS of 0 as determined by the Adjudication Committee; * No administration of glucocorticoids given for ANCA-associated vasculitis within 4 weeks prior to Week 26; * No BVAS \>0 during the 4 weeks prior to Week 26 (if collected for an unscheduled assessment).
次要结局
- Change From Baseline in Vital Signs (1/5)(Baseline, Week 26 and 52)
- Change From Baseline in Vital Signs (3/5)(Baseline, Week 26 and 52)
- Change From Baseline in Vital Signs (4/5)(Baseline, Week 26 and 52)
- Change From Baseline in Vital Signs (5/5)(Baseline, Week 26 and 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (2/5)(Baseline, Week 26 and 52)
- Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs(From day 1 throughout the study period (day 421/week 60))
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (4/5)(Baseline, Week 26 and 52)
- Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving BVAS=0 at Any Time During the Treatment Period(Week 52)
- Percentage of Participants With BVAS of 0 at Week 4, Regardless of Whether the Subjects Received Glucocorticoids During This Period of Time and Based on Assessment by the Blinded AC(Week 4)
- Change From Baseline Over 52 Weeks in Health-related Quality of Life as Measured by the Domains and Component Scores of the SF-36v2 and EQ-5D-5L VAS and Index(Baseline, Week 26 and 52)
- Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving Remission at Week 26 in the Study(Week 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (3/5)(Baseline, Week 26 and 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (2/2)(Baseline, Week 26 and 52)
- Change From Baseline in Vital Signs (2/5)(Baseline, Week 26 and 52)
- Number of Subjects With Clinically Significant ECG Changes From Baseline(From day 1 throughout the study period (day 421/week 60))
- Glucocorticoid-induced Toxicity as Measured by Change From Baseline Over the First 26 Weeks in the GTI(Baseline, Week 13 and 26)
- Change in the VDI From Baseline Over 52 Weeks, Including the Week 26 and Week 52 Time Points(Baseline, Week 26 and 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (1/5)(Baseline, Week 26 and 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (5/5)(Baseline, Week 26 and 52)
- In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Change in eGFR From Baseline Over 52 Weeks(Baseline, Week 26 and 52)
- In Subjects With Renal Disease and Albuminuria at Baseline (Based in the BVAS Renal Component), the Percent Change in UACR From Baseline Over 52 Weeks(Baseline, Week 4, 26 and 52)
- In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Percent Change in Urinary MCP-1:Creatinine Ratio From Baseline Over 52 Weeks(Baseline, Week 26 and 52)
- Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (1/2)(Baseline, Week 26 and 52)
- Number of Subjects Where a Relationship Between Avacopan/Placebo, Glucocorticoid Use, Cyclophosphamide, Rituximab, and Azathioprine or Mycophenolate Use to an AE Was Determined by the Investigator(From day 1 throughout the study period (day 421/week 60))
- Certain Safety Endpoints of Interest: Infections, Hepatic System Abnormalities, WBC Count Decreases, and Hypersensitivity(From day 1 throughout the study period (day 421/week 60))
- Number of Subjects Experiencing a Relapse After Previously Achieving BVAS=0 During the Study(From day 1 throughout the study period (day 421/week 60))