Avacopan Added to Standard-of-care Therapy in ANCA-associated Vasculitis With Severe Kidney Involvement

Официальное название

Avacopan Added to Standard-of-care Therapy in ANCA-associated Vasculitis With Severe Kidney Involvement: a Randomized, Placebo-controlled, Double-blinded Multicenter Superiority Study

Обзор

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.

Вмешательства

• Препарат Avacopan
  At day 0, and weeks 4, 8, 12, 20 36 patients will have avacopan dispensation
• Препарат Placebo
  At day 0, and weeks 4, 8, 12, 20 36 patients will have placebo dispensation

Первичные конечные точки

• Improvement in the kidney function [Срок оценки: Day 0 and 52 weeks after randomization]

Вторичные конечные точки (8)

• Survival in both groups [Срок оценки: Day 0, 52 and 64 weeks after randomization]
• Assessment of vasculitis activity [Срок оценки: Day 0, 20, 52 and 64 weeks after randomization]
• Assessment of kidney function [Срок оценки: Day 0, 20, 52 and 64 weeks after randomization]
• the proportion of end-stage kidney disease [Срок оценки: Day 0, 20, 52 and 64 weeks after randomization]
• the evolution of the kidney inflammation [Срок оценки: Day 0, 4, 12, and 52 weeks after randomization]
• Changes in quality of life [Срок оценки: Day 0 and 64 weeks after randomization]
• The assessment the ability of kidney biopsy results to predict the renal response to avacopan [Срок оценки: Day 0, 20 and 52 weeks after randomization]
• Safety of treatment [Срок оценки: Day 0 and 64 weeks after randomization]

Критерии участия

Критерии включения

• 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)
• Affiliated person or beneficiary of a social security scheme.
• Free, informed and written consent signed by the participant and the investigator
• For women able to procreate, ongoing effective contraception

Критерии исключения

• • 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.
• Pregnant 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): Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (Oral, Intravaginal, Transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (Oral, Injectable, Implantable); Intrauterine device (IUD); Intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomised partner.
• 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)

• Patients 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
• Co-administration of strong CYP3A4 enzyme inducers
• Known allergy to avacopan
• 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.
• Human immunodeficiency virus (HIV) positivity.
• Acute or chronic infection with hepatitis B (HBV) or hepatitis C (HCV).
• 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.
• 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.
• 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.
• 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
• 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).
• Severe heart failure history (i.e., LVEF < 30%)
• Solid organ transplantation
• 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.
• Patient under legal protection.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Франция · 30 центров

• Amiens Hospital — Amiens
• Angers Hospital — Angers
• Besançon Hospital — Besançon
• Bordeaux Hospital — Bordeaux
• Boulogne-sur-Mer Hospital — Boulogne-sur-Mer
• Brest Hospital — Brest
• Caen Hospital — Caen
• Grenoble Hospital — Grenoble
• … и ещё 22 центра

Идентификаторы

NCT: NCT07373262 · RC31/24/0321 · 2024-519620-24-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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