AVACOPAN for ANCA-associated vasculitis

Inclusion criteria

• {"criterion_text":"-Are male or female, 18 to 85 years of age\n-Kidney biopsy before inclusion available (up to 6 weeks before inclusion) or patients agreeing to have a renal biopsy procedure performed no later than prior the visit at week 4\n-Have been newly diagnosed or relapsing active AAV-related RPGN at the time of inclusion (either granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), according to the American College of Rheumatology/European League Against Rheumatism 2022 (ACR/EULAR 2022) classification criteria, with or without positive ANCA testing)\n-Have an active disease (BVAS ≥ 3, with at least one of the 2 renal items of proteinuria (urinary proteinuria/creatininury > 300 mg/g) and haematuria (>10 RBC/hpf) within the BVAS), and eGFR 0-29 mL/min/1.7 m2 at inclusion\n-Be planned to receive a SOC induction regimen by rituximab or cyclophosphamide plus glucocorticoids (+ or - plasma exchanges) for the current AAV flare (rituximab or cyclophosphamide may have been started before the inclusion in the study, maximum 2 weeks before the inclusion)\n-Affiliated person or beneficiary of a social security scheme.\n-Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research).\n-For women able to procreate, ongoing effective contraception"}

Exclusion criteria

• {"criterion_text":"-Irreversible medical conditions likely to affect short-term survival or ability to participate in the study protocol\n-Solid organ transplantation\n-Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.\n-Treatment by >3000 mg methylprednisolone or equivalent within the 3 weeks preceding the screening visit\n-Pregnancy or breastfeeding\n-Patient under legal protection.\n-Known eGFR before the AAV flare already <35 mL/min/1.73m2\n-Glomerulosclerosis >60% or kidney interstitial fibrosis >60%, if results of a kidney biopsy are available. If kidney biopsy is performed after inclusion in the study, the patients will continue the study according to the protocol whatever the extent of glomerulosclerosis or interstitial fibrosis.\n-•\tPregnant or breast-feeding women, or desire to become pregnant within 24 months. All women of childbearing potential (WOCBP) are required to have a negative pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using an effective method of birth control from the date of consent through the end of the study and another 12 months after (or 12 months after the last rituximab infusion in case of premature termination)\n-Hepatic dysfunction defined as: ALT, AST or alkaline phosphatase > 3 ×ULN Total Bilirubin >2 × ULN, with the exception of participants with Gilbert syndrome who may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN International normalized ratio (INR) >1.7 (excepted if patient receive vitamin K antagonists)\n-Co-administration of strong CYP3A4 enzyme inducers\n-Human immunodeficiency virus (HIV) positivity.\n-Known allergy to avacopan\n-Other clinically active systemic autoimmune disease requiring therapy, including but not limited to: eosinophilic granulomatosis with polyangiitis (EGPA), moderate to severe systemic lupus erythematosus, IgA vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjögren's syndrome, cryoglobulinemic vasculitis, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome or mixed connective tissue disease.\n-•\tPatients with leukocytes below 2000/mm3 or neutrophils below 1000/mm3 will be excluded. However, since patients may have received rituximab or cyclophosphamide before inclusion as a part of induction regimen of the AAV (see inclusion criteria), and both are considered as lymphodepleting agent, mild to moderate lymphopenia (400 – 1500/mm3) at randomization will be allowed\n-Acute or chronic infection with hepatitis B (HBV) or hepatitis C (HCV\n-Positive serology for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) excludes the participant regardless of detection of hepatitis B surface antibodies (HBsAb) or HBV-DNA\n-Participants with a positive HCV antibody test should have HCV ribonucleic acid (RNA) levels measured. Participants with positive (detectable) HCV RNA must be excluded. Chronic hepatitis C participants, who have completed anti- HCV treatment for at least 12 weeks must have a negative HCV RNA result before randomization. Cases of spontaneous HCV clearance should be discussed with sponsor before enrolment.\n-Active viral, bacterial or other infections requiring systemic treatment, or history of recurrent clinically significant infection which in the opinion of the investigator will place the participant at risk for participation.\n-Uncontrolled diabetes mellitus, lung diseases or any other illnesses not related to GPA/ MPA that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate glucocorticoids\n-History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 3 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed).\n-Severe heart failure history (i.e., LVEF < 30%)"}

Primary endpoints

• {"endpoint_text":"-Proportion of patients reaching an estimated glomerular filtration rate > or =30 mL/min/1.7m² (CKD-EPI formula applied to the measure of standardized serum creatinine) at week 52 without requiring treatment study discontinuation for serious adverse event or treatment modification or intensification for refractory vasculitis or relapse","definition_or_measurement_approach":"eGFR calculated using CKD-EPI formula from standardized serum creatinine; assessed at week 52; composite requirement: eGFR ≥ 30 mL/min/1.73m² and no treatment discontinuation for SAE or treatment modification/intensification for refractory vasculitis or relapse."}

Secondary endpoints

• {"endpoint_text":"-Survival (at week 52 and 64; % and survival curves)\n-Birmingham Vasculitis Activity Score (BVAS; evaluation at weeks 0, 20, 52, 64) and Vasculitis Damage Index (change between baseline (week 0) and weeks 20, 52 and 64, respectively)\n-Proportion of patients achieving disease remission (defined as BVAS score = 0) at weeks 20, 52 and 64\n-Changes in eGFR from baseline (in mL/min/1.7m2; CKD-EPI formula derived from the serum creatinine) and weeks 20, 52 and 64, respectively\n-Urinary protein/creatinine ratio (mg/mmol) and urinary albumin/creatinine ratio (mg/mmol) at week 20, 52 and 64\n-Number and percentage of patients requiring chronic dialysis at weeks 20, 52 and 64\n-Urinary levels of MCP-1 and soluble CD163\n-Urinary and serum levels of C3a, C5a and factor Bb (evaluation at inclusion and at weeks 4, 12, 20, and 52)\n-Short Form-36 v.2 component and domain scores and the EuroQOL-5D-5L visual analogue scale (in mm) and index: change between baseline and week 64\n-Brix / Berden scores, C3 deposits in glomeruli, interstitial fibrosis, glomerulosclerosis, percentage of extra-capillary crescents measured at baseline\n-Occurrence of infections, diabetes mellitus, hepatitis and other adverse events (inclusion to week 64)","definition_or_measurement_approach":"Endpoints include timepoint-specific assessments (weeks indicated in each endpoint). Survival assessed as % and Kaplan-Meier curves at weeks 52 and 64. BVAS and VDI measured at specified weeks. Remission defined as BVAS = 0. eGFR changes calculated using CKD-EPI. Protein/albumin creatinine ratios measured in urine at specified weeks. Dialysis requirement counted at specified weeks. Biomarkers (MCP-1, soluble CD163, C3a, C5a, factor Bb) measured in urine/serum at inclusion and scheduled weeks. QoL via SF-36 v2 and EQ-5D-5L change to week 64. Histology scores assessed at baseline. Safety events collected from inclusion to week 64."}

France

Earliest CTIS Part Ii Submission Date

09-10-2025

Latest Decision Or Authorization Date

27-11-2025

Processing Time Days

49

Number Of Sites

30

Number Of Participants

130

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Toulouse

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France