ANCA-associated vasculitis (AAV) is a rare auto-immune disease, with high mortality in the absence of treatment. There is still an unmet need to define new treatment strategies to reduce drug side effects, as well as to reverse rare cases of refractory AAV and improve the kidney response to improve the long-term outcomes.
Severe forms of AAV-related necrotizing and crescentic rapidly progressive glomerulonephritis (RPGN) (i.e. estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m²) are associated with higher mortality, higher incidence of infections, and long-term consequences including chronic kidney disease (CKD) with subsequent complications (end-stage kidney disease (ESKD) requiring dialysis, cardiovascular diseases) and a burden of financial costs.
In patients with AAV and RPGN, recent guidelines recommend using a standard-of-care (SOC) immunosuppressive regimen including an induction regimen (rituximab or cyclophosphamide), plus glucocorticoids (GCs) (starting at 60 mg/day and tapering over 6-12 months) (+ or - plasma exchanges).
Since GCs also participate to the long-term control of AAV, new molecular pathophysiology-driven therapeutic approaches rapidly blocking and/or reversing AAV lesions are needed to go beyond the progressive control of AAV using GCs alone. Thus, an add-on approach including GCs-based immunosuppressive regimen plus a new targeted therapy may lead to both AAV control (systemic disease) and improvement of the kidney outcome (organ involvement).
Avacopan a selective inhibitor of the C5a receptor, recently emerged as a new therapeutic option in AAV. In a phase 3 comparative study (that included a small subset of patients with eGFR 15-29 mL/min/1.7m2), avacopan was superior to glucocorticoids taper with respect to sustained remission at week 52. In the avacopan arm, the cumulative dose of GCs was dramatically reduced and avacopan was thus proposed as an alternative to GCs rather to a synergic treatment. In the subgroup of patients with eGFR \<30 mL/min/1.73m², avacopan was associated with a better eGFR gain at week 52 compared to prednisone, but data in this population at-risk of worse kidney outcomes are scarce, and did not include patients with eGFR \< 15 mL/min/1.73m², those patients being excluded from the study.
In the REVERSE study, investigators put forward the hypothesis that avacopan added on GCs regimen may significantly improve the kidney outcome of severe AAV (synergic approach), and thus improve short- and long-term global outcomes (survival, cardiovascular status). REVERSE will thus compare GCs-based SOC + placebo to GCs-based SOC + avacopan.
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
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)
Have an active disease (BVAS ≥ 3, with at least one of the 2 renal items of proteinuria (urinary proteinuria/creatininuria > 300 mg/g) and haematuria (>10 RBC/hpf) within the BVAS), and eGFR 0-29 mL/min/1.7 m2 at inclusion
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)
• Irreversible medical conditions likely to affect short-term survival or ability to participate in the study protocol
Treatment by >3000 mg methylprednisolone or equivalent within the 3 weeks preceding the screening visit
Known eGFR before the AAV flare already <35 mL/min/1.73m2
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.
Parallel
Avacopan
DrugAt day 0, and weeks 4, 8, 12, 20 36 patients will have avacopan dispensation
Placebo
DrugAt day 0, and weeks 4, 8, 12, 20 36 patients will have placebo dispensation
Improvement in the kidney function
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.
Survival in both groups
percentage of patients alive (and Kaplan Meier survival curves)
Assessment of vasculitis activity
The vasculitis activity is a composite measure derived from 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)
Assessment of kidney function
The kidney function is a composite measure derived from changes in eGFR from baseline (in mL/min/1.7m2; CKD-EPI formula derived from the serum creatinine) and Urinary protein/creatinine ratio (mg/mmol) and urinary albumin/creatinine ratio (mg/mmol)
the proportion of end-stage kidney disease
the proportion of end-stage kidney disease is a composite measure derived from number and % percentage ofpatients requiring chronic dialysis
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