ERKNet

The European Rare Kidney Disease Reference Network

  

Research Project

Project Title:

A randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of Avacopan (CCX168) in patients with C3 glomerulopathy (CL011_168 trial)

Project Type:

Clinical Trial, Enrolment ongoing

Disease group(s):

Hereditary glomerulopathies, Immune glomerulopathies

Project Summary:

Purpose
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).

Primary Outcome
Histologic Index: Percent change from baseline in the C3G Histologic Index for disease activity.

Secondary Outcomes
- Histologic response: the proportion of subjects who have a histologic response defined as a decrease (improvement) in the C3G Histologic Index for activity at 26 weeks.
- Histologic Index: the percent change from baseline in the C3G Histologic Index for disease chronicity over the placebo-controlled treatment period.
- eGFR: the change from baseline in eGFR over the placebo-controlled treatment period.
- eGFR: the percent change from baseline in eGFR over the placebo-controlled treatment period.
- UPCR: The percent change from baseline in UPCR over the placebo-controlled treatment period.
- Urinary MCP-1: The percent change from baseline in urinary MCP-1: creatinine ratio over the placebo-controlled treatment period.
- EQ-5D-5L: Change from baseline in EQ-5D-5L (visual analogue scale and index) over the placebo-controlled treatment period.
- SF-36 v2: Change from baseline in SF-36 v2(domains and component scores) over the placebo-controlled treatment period.

Estimated Enrollment: 44

Inclusion criteria
1. 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: 1) >=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 2) 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 3) confirmation of the presence of electron dense deposits in the glomeruli on electron microscopy corresponding with the C3 immunofluorescence positivity.
2. Plasma soluble C5b-9 level >244 ng/mL, the upper limit of the reference range of the central laboratory.
3. 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).
4. 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
5. 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.

Exclusion criteria
1. Pregnant or nursing.
2. Tubulointerstitial fibrosis appears to be more than 50% based on standard assessment using trichrome staining of the renal biopsy.
3. Use of eculizumab or another anti-C5 antibody within 26 weeks prior to dosing.
4. 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.
5. Currently on dialysis or likely will require dialysis within 7 days after screening.
6. 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.
7. Positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) viral screening test indicative of acute or chronic infection.
8. 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.
9. WBC count less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte count less than 500/μL before start of dosing.
10. Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the upper limit of normal before start of dosing.
11. Currently using a strong inducer of the CYP3A4 enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John's wort.
12. Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules (including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the capsules.
13. 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
14. 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.

Lead principal investigator(s):

Giuseppe Remuzzi, Bergamo

Project Period:

09/2017   -   10/2019

Sponsors:

Industry

ClinicalTrials.gov:

NCT03301467

EudraCT Nr.:

2017-001821-42

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