A Randomized, Double Blind, Placebo Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Avacopan (CCX168) in Patients With C3 Glomerulopathy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 57
- 试验地点
- 4
- 主要终点
- Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9
研究概览
简要总结
The aim of this trial is to evaluate the effect of avacopan treatment on renal disease activity in patients with complement component 3 glomerulopathy (C3G). Funding Source - FDA OOPD
详细描述
C3 glomerulopathy (C3G) is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli. There are two forms of the disease: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). There is no approved treatment for patients with C3G.
This is a randomized, double blind, placebo controlled Phase 2 study to evaluate the safety and efficacy of avacopan (CCX168) in patients with C3G. Patients receive avacopan 30mg or matching placebo orally twice-daily. The placebo-controlled treatment period is 26 weeks (182 days). This will be followed by 26 weeks during which time all patients will receive avacopan (results for this second period will be reported in due course in a follow-up publication). Thereafter, all patients will be followed for eight weeks (56 days) without study drug treatment. The primary objective is to evaluate the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies taken at baseline and after 26 weeks of treatment. The primary endpoint will be based on the percent change from baseline in the C3G Histologic Index for disease activity.
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
Matching placebo
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
- •Biopsy-proven C3G, either DDD or C3GN, with or without a renal transplant, and with the following observations upon renal biopsy taken within 12 weeks prior to screening or during screening:
- •≥2-levels of magnitude greater staining of C3 than any combination of IgG, IgM, IgA, kappa and lambda light chains, and C1q by immunohistochemistry, and
- •evidence of proliferative glomerulonephritis (mesangial hypercellularity of greater than 3 mesangial cells per mesangial area and/or endocapillary hypercellularity defined as an increased number of cells within glomerular capillary lumina, causing luminal narrowing) based on light microscopy, and
- •confirmation of the presence of electron dense deposits in the glomeruli on electron microscopy corresponding with the C3 immunofluorescence positivity;
- •Male or female subjects, aged at least 18 years; where approved, adolescents (12-17 year old) may be enrolled; female subjects of childbearing potential (i.e., those who have experienced menarche and who is not permanently sterile or postmenopausal, defined as at least 12 consecutive months with no menses without an alternative medical cause) may participate if adequate contraception is used during, and for at least the three months after study completion; Male subjects with partners of childbearing potential may participate in the study if they had a vasectomy at least 6 months prior to randomization or if adequate contraception is used during, and for at least the 3 months after study completion; Adequate contraception is defined as resulting in a failure rate of less than 1% per year (combined estrogen and progestogen [oral, intravaginal, or transdermal], or progestogen-only hormonal contraception (oral, injectable, or implantable), intra-uterine device, intra-uterine hormone releasing system, bilateral tubal occlusion, vasectomized partner, or true sexual abstinence, i.e., in line with the preferred and usual lifestyle of the subject);
- •Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; written Assent and Informed Consent must be obtained from the legal guardian in accordance with regional laws or regulations for subjects 12 to 17 years of age; and
- •Judged to be otherwise fit for the study by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Subjects with clinical laboratory values that are outside of normal limits (other than those specified in the Exclusion Criteria) and/or with other abnormal clinical findings that are judged by the Investigator not to be of clinical significance, may be entered into the study.
排除标准
- •Pregnant or nursing;
- •Tubulointerstitial fibrosis appears to be more than 50% based on standard assessment using trichrome staining of the renal biopsy;
- •Use of eculizumab or another anti-C5 antibody within 26 weeks prior to dosing;
- •Secondary C3 disease, e.g., infection-associated disease, or associated with another systemic or autoimmune disease; presence of a monoclonal spike on serum or urine protein electrophoresis or immunofixation assay;
- •Currently on dialysis or likely will require dialysis within 7 days after screening;
- •History or presence of any form of cancer within the 5 years prior to screening, with the exception of excised basal cell or squamous cell carcinoma of the skin, or carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis;
- •Positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) viral screening test indicative of acute or chronic infection;
- •Evidence of tuberculosis based on interferon γ release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography done at screening or within 6 weeks prior to screening;
- •WBC count less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte count less than 500/μL before start of dosing;
- •Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the upper limit of normal before start of dosing;
- •Currently using a strong inducer of the CYP3A4 enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John's wort;
- •Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules (including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the capsules;
- •Participated in any clinical study of an investigational product within 30 days prior to screening or within 5 half-lives after taking the last dose; and
- •History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation.
研究组 & 干预措施
Avacopan
Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26 week blinded treatment period
干预措施: Avacopan (Drug)
Avacopan Matching Placebo
Matching placebo capsules x 3 administered twice daily during the 26 week blinded treatment period period
干预措施: Avacopan Matching Placebo (Drug)
结局指标
主要结局
Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9
时间窗: Week 26
Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Subjects with Elevated C5b-9 (\> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy
Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Combined C5b-9 Strata
时间窗: Week 26
Percent change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Combined C5b-9 Strata (elevated \[\> 244 ng/mL\] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy \* Multiple Imputation: Missing Week 26 values are imputed using the regression method to create 100 complete datasets.
次要结局
- Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Subjects With Elevated C5b-9(Week 26)
- Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Combined C5b-9 Strata(Week 26)
- Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Subjects With Elevated C5b-9(Week 26)
- Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Combined C5b-9 Strata(Week 26)
- Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9(Week 26)
- Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata(Week 26)
- Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9(Week 26)
- Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata(Week 26)
- Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Subjects With Elevated C5b-9(Week 26)
- Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Combined C5b-9 Strata(Week 26)
- Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Subjects With Elevated C5b-9(Week 26)
- Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Combined C5b-9 Strata(Week 26)
- Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects With Elevated C5b-9(Week 26)
- Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata(Week 26)
- Change From Baseline Over 26 Weeks in SF-36 v2 - Subjects With Elevated C5b-9(Week 26)
- Change From Baseline Over 26 Weeks in SF-36 v2 - Combined C5b-9 Strata(Week 26)
- Number of Subjects With Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs(From day 1 throughout the study period (day 182/week 26))
- Number of Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs(From day 1 throughout the study period (day 182/week 26))