C3 Glomerulopathy
Conditions
Interventions
The subjects will be randomized 1:1 to receive 30 mg avacopan twice daily or
matching placebo for 26 weeks in a double-blind, placebo-controlled manner. The
primary efficacy analysis will occur when
Sponsors
Chemocentryx
Eligibility
Age
12 Years to 99 Years
Inclusion criteria
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: a. >=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 b. 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 c. confirmation of the presence of electron dense deposits in the glomeruli on electron microscopy corresponding with the C3 immunofluorescence positivity; 2. Male or female patients, aged at least 18 years; where approved, adolescents (12-17 year old) may be enrolled; female patients 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 patients with partners of childbearing potential may be excluded if they plan to father a child during the study; 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 patient. In addition, a barrier method (i.e., cervical cap, diaphragm or condom) must be used during intercourse between a male patient and a female of child-bearing potential; 3. 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 patients 12 to 17 years of age; and 4. Judged to be otherwise fit for the study by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Patients 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. At sites in which adolescents are allowed to be enrolled, the Investigator assures that the adolescent patient is willing and able to ingest the size "0" study drug.
Exclusion criteria
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 HBV, HCV, or 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; a CT scan or chest X-ray are not mandatory if evidence of tuberculosis was excluded by any of the other methods specified above; 9. Active uncontrolled infection; 10. WBC count less than 3500/mL, or neutrophil count less than 1500/mL, or lymphocyte count less than 500/mL before start of dosing; 11. Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the upper limit of normal before start of dosing; 12. Currently using a strong inducer of the cytochrome P450 3A4 (CYP3A4) enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John*s wort; 13. Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules (including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the capsules; 14. 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 15. History or presence of any medical condition (for example: contraindication to local anesthesia required for renal biopsy, or recurring serious infections) or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary efficacy endpoint is the percent change from baseline to Week 26 in the C3G Histologic Index for disease activity. | — |
Secondary
| Measure | Time frame |
|---|---|
| Other efficacy endpoints include: 1. The proportion of patients who have a histologic response, defined as a decrease (improvement) in the C3G Histologic Index for activity of at least 35% from baseline to Week 26; 2. The percent change from baseline in the C3G Histologic Index for disease chronicity over the placebo-controlled 26-week treatment period; 3. The change and percent change from baseline in eGFR over the placebo-controlled 26-week treatment period; 4. The percent change from baseline in UPCR over the placebo-controlled 26-week treatment period; 5. The percent change from baseline in urinary MCP-1:creatinine ratio over the placebo-controlled 26-week treatment period; 6. Change from baseline in EQ-5D-5L (visual analogue scale and index) and SF-36 v2 (domains and component scores) over the placebo-controlled 26-week treatment period. Safety endpoints include: 1. Patient incidence of treatment-emergent serious adverse events, adverse events, and study withdrawals due to adverse events; 2. Change from baseline and shifts from baseline in all safety laboratory parameters; 3. Change from baseline in vital signs. | — |
Countries
Netherlands
Outcome results
None listed