Overview

The purpose of this study is to evaluate the efficacy and safety of Avacopan together with low-dose glucocorticoid in the treatment of patients with crescentic Imunoglobulin A Nephropathy (IgAN) and high risk of progression.

Eligibility

Inclusion Criteria

• Age > 18 years
• Kidney biopsy showing crescentic IgA nephropathy within 6 months of enrolment (MEST-C-score =C1/C2).
• Quantified creatinine clearance >20 ml/min/1.73m2
• Quantified Proteinuria > 750 mg/24h based on a 24h urine collection while on maximum tolerated dose of RAS blockade
• Hematuria defined as >10 RBC/hpf or hemoglobinuria >1+
• Patients need to be in adequate supportive care (blood pressure <125/85mmHg, lifestyle advice, and maximum doses tolerable of RAS blockade) at least 4 weeks prior to enrollment
• Patients would receive dietary and lifestyle counseling prior enrollment: low protein (0.8-1.0 g/kg/day) diet, low sodium (2 grams/day) intake, indication for smoke cessation, during the 4 weeks run-in period
• Has signed an informed consent form prior to any study-related procedures
• Patients with documented use of RAS blockade and adequate blood pressure control (<125/85 mmHg) for ≥4 weeks, can be enrolled in the study and randomized without repeating a 4-week run-in period.

Exclusion Criteria

• Creatinine clearance <20 ml/min/1.73 m2
• Liver function tests > 2x upper limit of normal. (Serious cases of hepatotoxicity have been reported in patients with avacopan during first approval and ADVOCATE study (29) (30)
• Severe interstitial fibrosis and tubular atrophy (IFTA > 70% on renal biopsy)
• Active cancer or acute non-controlled infection (including HIV, HBV, HCV)
• Women who are pregnant or breastfeeding
• Immunosuppression treatment:
• Rituximab less than 12 months prior to enrollment
• MMF, CYC, or immunomodulatory agents within 3 months prior to enrollment
• AZA within 3 months prior to enrollment.
• Glucocorticoids >20 mg/day within 1 month prior to enrollment
• Secondary IgA nephropathy (associated with gastrointestinal diseases, infection, autoimmune, malignancy, respiratory tract, or skin)
• ANCA-associated vasculitis or other vasculitis diagnostic defined by ACR criteria/Chapel Hill Consensus conference
• Contraindication to use any of the protocol treatments (glucocorticoids, avacopan)
• Use of a strong/moderate CYP3A4 inducer
• Initiation of SGLT2 inhibitors is not allowed once patient has been enrolled in the study. Patients who have been on an SGLT2 inhibitor prior to enrollment on the study may continue on this therapy, at the same dose. No dose increase is allowed.
• Active, untreated and/or uncontrolled chronic liver disease (chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis, cirrhosis
• Unable to give written consent form
• As a safety measure patients who are pregnant or lactating will not be enrolled in the study.