Avacopan added to standard-of-care therapy in ANCA-associated vasculitis with severe kidney involvement: a randomized, placebo-controlled, double-blinded multicenter superiority study

The primary objective is to demonstrate improvement in kidney function at week 52, defined as achieving an estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73m² (corresponding to chronic kidney disease stage 1-3), in patients with severe forms of ANCA-associated vasculitis presenting with rapidly progressive glomerulonephritis (baseline eGFR 0-29 mL/min/1.73m²) when avacopan is added to glucocorticoid-based standard-of-care therapy. This objective addresses a critical clinical need in patients with advanced renal impairment secondary to ANCA-associated vasculitis, where preservation or improvement of kidney function directly impacts long-term outcomes and dialysis dependency.

The secondary objectives include:

• Assessment of survival in both treatment groups up to week 64

• Evaluation of vasculitis activity using the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI) at weeks 20, 52, and 64

• Assessment of treatment-related adverse events occurrence in both groups

• Evaluation of kidney function parameters (eGFR and proteinuria) at weeks 20, 52, and 64

• Determination of the proportion of patients progressing to end-stage kidney disease requiring chronic dialysis at weeks 20, 52, and 64

• Assessment of kidney inflammation intensity through urinary levels of soluble CD163 and MCP1, as well as urinary and serum levels of C3a, C5a, and factor Bb at inclusion and weeks 4, 12, 20, and 52

• Evaluation of changes in quality of life from baseline to week 64

• Assessment of kidney biopsy predictive capacity for renal response to avacopan in patients receiving avacopan (per-protocol analysis)

• Conservation of blood and urine samples for future biological analyses

The sponsor does not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes both **male** and **female** participants aged **18 to 85 years**. Participants are individuals with newly diagnosed or relapsing **ANCA-associated vasculitis** presenting with **rapidly progressive glomerulonephritis**, specifically **granulomatosis with polyangiitis** or **microscopic polyangiitis**. The trial population was selected based on the presence of active disease with specific renal manifestations including **proteinuria** and **haematuria**, and significantly impaired kidney function defined by an **estimated glomerular filtration rate** of 0-29 mL/min/1.73m² at inclusion, corresponding to **chronic kidney disease** stage 4-5. Participants must have a **kidney biopsy** available or agree to undergo this procedure. All participants are planned to receive standard of care induction therapy consisting of **rituximab** or **cyclophosphamide** combined with **glucocorticoids**, with or without **plasma exchanges**. Female participants of childbearing potential are required to use effective contraception throughout the study period.

This is a randomized, placebo-controlled, double-blind, multicenter superiority clinical trial designed to evaluate the efficacy and safety of **avacopan** when added to standard-of-care therapy in patients with **ANCA-associated vasculitis** presenting with severe kidney involvement. The study is classified as a **Phase III trial** and employs a **low-intervention design**. Participants will be randomized to receive either avacopan or placebo in addition to standard induction therapy consisting of **rituximab** or **cyclophosphamide** combined with **glucocorticoids**, with or without plasma exchanges. The primary objective is to demonstrate improvement in kidney function at week 52, defined as achieving an **estimated glomerular filtration rate** of 30 mL/min/1.73m² or greater without requiring treatment discontinuation due to serious adverse events or treatment modification for refractory vasculitis or relapse.

The trial involves both newly diagnosed and relapsing patients aged 18 to 85 years with active ANCA-associated vasculitis-related **rapidly progressive glomerulonephritis**, defined by a **Birmingham Vasculitis Activity Score** of 3 or greater and an eGFR between 0 and 29 mL/min/1.73m² at inclusion. Eligible participants must have either **granulomatosis with polyangiitis** or **microscopic polyangiitis** according to ACR/EULAR 2022 classification criteria. A kidney biopsy must be available within six weeks prior to inclusion or performed no later than the week 4 visit. Patients must be planned to receive standard induction therapy, which may have been initiated up to two weeks before study inclusion. Female participants of childbearing potential must maintain effective contraception throughout the trial.

The investigational medicinal product avacopan (AMG 569) will be administered orally in capsule form at a maximum daily dose of 60 mg, with a maximum total dose of 21,900 mg over a treatment period of up to 52 weeks. The matching placebo will be administered to the control group following the same schedule. Auxiliary medications include **rituximab** administered by infusion at a maximum dose of 375 mg/m², **cyclophosphamide** administered orally at a maximum daily dose of 1,000 mg for up to 12 weeks, **methylprednisolone** administered orally at a maximum daily dose of 1,000 mg for up to 20 weeks, and oral **prednisone** or **prednisolone** at a maximum daily dose of 80 mg for up to 20 weeks. All investigational and auxiliary products are synthetic in origin.

The primary endpoint is the proportion of patients achieving an eGFR of 30 mL/min/1.73m² or greater at week 52, calculated using the CKD-EPI formula applied to standardized serum creatinine measurements, without requiring treatment discontinuation for serious adverse events or treatment modification for refractory disease or relapse. Secondary endpoints include survival rates at weeks 52 and 64, changes in Birmingham Vasculitis Activity Score and **Vasculitis Damage Index** from baseline to weeks 20, 52, and 64, proportion of patients achieving disease remission defined as a BVAS score of zero, changes in eGFR from baseline, urinary protein-to-creatinine ratio and albumin-to-creatinine ratio, number and percentage of patients requiring chronic dialysis, urinary levels of MCP-1 and soluble CD163, urinary and serum levels of complement components C3a, C5a and factor Bb, quality of life assessments using Short Form-36 version 2 and EuroQOL-5D-5L instruments, histopathological parameters including Brix/Berden scores, C3 deposits in glomeruli, interstitial fibrosis, glomerulosclerosis, and percentage of extracapillary crescents, as well as occurrence of infections, diabetes mellitus, hepatitis, and other adverse events.

The estimated recruitment start date is January 2026, with an estimated study completion date of January 2031. Participant involvement extends from the screening and inclusion visit through week 64, representing the end-of-study visit. The screening visit includes confirmation of eligibility criteria, baseline assessments of disease activity using BVAS, measurement of eGFR, urinary protein and albumin ratios, collection of biological samples for biomarker analysis, and quality of life questionnaires. Follow-up visits are scheduled at weeks 4, 12, 20, 52, and 64 to monitor disease activity, kidney function, safety parameters, and collect samples for biomarker evaluation. The week 52 visit represents the primary endpoint assessment, while the week 64 visit serves as the end-of-study evaluation. Early termination from the study may occur due to serious adverse events requiring treatment discontinuation, treatment modification or intensification for refractory vasculitis or disease relapse, participant withdrawal of consent, pregnancy, loss to follow-up, or investigator decision based on safety concerns.

The experimental medication AMG 569 contains the active substance **avacopan** and is administered in capsule form via the **oral route**. The maximum daily dose is 60 milligrams, with a maximum total dose of 21,900 milligrams over a treatment period of up to 52 weeks. This investigational product is manufactured as a synthetic medicinal product and serves as the test intervention in this clinical trial.

A **placebo** for AMG 569 is included in the study design to enable blinded comparison with the experimental medication. The placebo is administered to maintain the double-blind nature of the trial and ensure that treatment allocation remains concealed from both participants and investigators throughout the study period.

**Rituximab** is administered as an auxiliary treatment in infusion form via the **intravenous route**. The maximum daily dose is 375 milligrams per square meter body surface area, with a maximum total dose of 375 milligrams per square meter. The maximum treatment period for rituximab is 4 weeks. This synthetic medicinal product is used as part of the standard-of-care therapy regimen.

**Cyclophosphamide** is provided as a solution for injection or infusion and is administered orally in this study. The maximum daily dose is 1,000 milligrams, with a maximum total dose of 1,000 milligrams. The maximum treatment period extends up to 12 weeks. This chemically-derived substance serves as an auxiliary treatment component within the standard-of-care protocol.

**Methylprednisolone** is administered as a solution for injection via the oral route. The maximum daily dose is 1,000 milligrams, with a maximum total dose of 1,000 milligrams over a maximum treatment period of 20 weeks. This synthetic **corticosteroid** is utilized as auxiliary therapy as part of the glucocorticoid-based standard-of-care regimen.

**Prednisone** is administered in tablet form via the oral route. The maximum daily dose is 80 milligrams, with a maximum total dose of 80 milligrams. The maximum treatment period is 20 weeks. This chemically-derived corticosteroid serves as an auxiliary medication within the standard-of-care therapy framework.

**Prednisolone** is provided in tablet form and administered orally. The maximum daily dose is 80 milligrams, with a maximum total dose of 80 milligrams over a maximum treatment period of 20 weeks. This synthetic corticosteroid functions as an auxiliary treatment component of the glucocorticoid-based standard-of-care therapy.

The primary endpoint is the proportion of patients achieving an estimated glomerular filtration rate of 30 mL/min/1.73 m² or greater at week 52, calculated using the CKD-EPI formula applied to standardized serum creatinine measurements, without requiring study treatment discontinuation due to serious adverse events or treatment modification or intensification for refractory vasculitis or relapse. Secondary endpoints include survival rates assessed at weeks 52 and 64, presented as percentages and survival curves. Disease activity and damage will be evaluated using the Birmingham Vasculitis Activity Score (BVAS) at weeks 0, 20, 52, and 64, and the Vasculitis Damage Index, with changes measured between baseline (week 0) and weeks 20, 52, and 64. The proportion of patients achieving disease remission, defined as a BVAS score of 0, will be assessed at weeks 20, 52, and 64. Changes in estimated glomerular filtration rate from baseline will be evaluated at weeks 20, 52, and 64 using the CKD-EPI formula derived from serum creatinine. Urinary protein-to-creatinine ratio and urinary albumin-to-creatinine ratio will be measured at weeks 20, 52, and 64. The number and percentage of patients requiring chronic dialysis will be determined at weeks 20, 52, and 64. Urinary levels of MCP-1 and soluble CD163, as well as urinary and serum levels of C3a, C5a, and factor Bb, will be evaluated at inclusion and at weeks 4, 12, 20, and 52. Quality of life assessments will include the Short Form-36 version 2 component and domain scores and the EuroQOL-5D-5L visual analogue scale and index, with changes measured between baseline and week 64. Histopathological parameters, including Brix/Berden scores, C3 deposits in glomeruli, interstitial fibrosis, glomerulosclerosis, and the percentage of extracapillary crescents, will be measured at baseline. The occurrence of infections, diabetes mellitus, hepatitis, and other adverse events will be monitored from inclusion through week 64.