Controlled Trial Evaluating Avacopan in C3 Glomerulopathy
Condition: C3 Glomerulopathy (C3G)
Intervention: Avacopan; Avacopan Matching Placebo
Intervention description: Orally administered; avacopan matching placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Placebo crossover to active
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Matching placebo
Enrollment: 57.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: C3 Glomerulonephritis; C3 glomerulopathy; C3G; DDD; dense deposit disease; membranoproliferative glomerulonephritis; MPGN; C3GN; idiopathic MPGN

Summary:

      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
    

Eligibility 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:

               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. 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);

          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 subjects 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. 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.