A Trial to Evaluate the Efficacy of Pioglitazone to Promote Renal Tolerance in ANCA-associated Vasculitis - RENATO Trial

Официальное название

A Multicenter Randomized Trial to Evaluate the Efficacy of Pioglitazone to Promote Renal Tolerance in ANCA-associated Vasculitis - RENATO

Обзор

The RENATO trial is a multicenter randomized controlled trial that evaluates the efficacy of pioglitazone to improve renal outcomes in ANCA-associated vasculitis. Patients with biopsy-proven kidney involvement of ANCA vasculitis will be included in this trial at diagnosis. All patients will receive a standard of care immunosuppressive (SOC) therapy combining corticosteroids and rituximab (375 mg/m2/week for 4 consecutive weals followed by 500 mg re-infusion every 6 months). They will be randomized 1:1 to receive either pioglitazone 30 mg/day or placebo for 6 months, on top of SOC. The primary objective of this trial is to demonstrate that pioglitazone reduces kidney damage, reflected by the early improvement of proteinuria and serum creatinine levels. The secondary objectives will be to assess the efficacy of this drug on the reduction of hypertension and metabolic effects of glucocorticoids, to measure its impact on vasculitis activity and to evaluate the safety profile of pioglitazone in this population.

Подробное описание

After a patient has consented to participate to the study, the informed consent form will be signed by the patient and the investigator. The patient will be randomized to one of two groups (pioglitazone or placebo). The patient will take the experimental treatment for 26 weeks and his research follow-up will last 52 weeks (follow-up visit : W1, W2, W3, W4 (research visit), W8, W12, W26, W38 and W52).

All participants will receive SOC immunosuppressive treatment with rituximab at 375 mg/m2/week for 4 consecutive weeks, as induction therapy of vasculitis flare, followed by 500 mg re-infusion every 6 months/24 weeks as maintenance therapy, i.e. at week 26 and 52, as recommended. The two treatment groups will also receive a standardized glucocorticoid tapering schedule: one to three i.v. pulses of methylprednisolone (7.5 to 15 mg/kg each) according to physician decision, followed by a predefined oral prednisone tapering schedule as used in the reduced-dose arm of the PEXIVAS trial.

Samples (plasma, serum and urine) taken as part of the study will be stored in a biological sample collection (at D0, W1, W2, W3, W12, W26, W38 and W52 visits).

Вмешательства

• Препарат Pioglitazone (ACTOS®)
  Patient will be randomize in the intervention group receive treatment by pioglitazone (30 mg/day orally) for 26 weeks on top of a SOC immunosuppressive treatment.
• Препарат Placebo of Pioglitazone
  Patient will be randomize in the intervention group receive treatment by placebo of pioglitazone (30 mg/day orally) for 26 weeks on top of a SOC immunosuppressive treatment.

Первичные конечные точки

• Appearance of a success defined as (1) Delta sCreat > 30% (between D0 and week 26) AND (2) urine protein-to-creatinine (uPCR) < 1g/mmol [Срок оценки: Week 26]

Вторичные конечные точки (12)

• Change of renal function [Срок оценки: Weeks 4, 12, 26 and 52]
• Proteinuria ratio [Срок оценки: Weeks 4, 12, 26 and 52]
• Score VDI (Vasculitis Damage Index) [Срок оценки: Week 26 and 52]
• Renal vasculitis activity [Срок оценки: Weeks 4, 12, 26 and 52]
• Renal vasculitis activity [Срок оценки: Weeks 4, 12, 26 and 52]
• Renal vasculitis activity [Срок оценки: Weeks 4, 12, 26 and 52]
• Renal vasculitis activity [Срок оценки: Weeks 4, 12, 26 and 52]
• Systemic vasculitis activity : score BVAS [Срок оценки: Weeks 4, 12, 26 and 52]
• Refractory vasculitis [Срок оценки: Weeks 12, 26 and 52]
• Improvement in Quality of Life (SF-36) [Срок оценки: baseline, weeks 4, 12, 26 and 52]
• Improvement in Quality of Life (EQ-5D) [Срок оценки: baseline, weeks 4, 12, 26 and 52]
• Safety profile of pioglitazone [Срок оценки: Weeks 26 and 52]

Критерии участия

Критерии включения

• Newly-diagnosed or relapsing ANCA-associated vasculitis, i.e. granulomatosis with polyangitis (GPA) or microscopic polyangiitis (MPA), according to ACR 1990 criteria and/or revised Chapel Hill Consensus Conference definitions and/or European Medical Agency algorithm, with an active disease defined as a BVAS ≥3
• Presence of proteinuria (UPCR >300 mg/g), haematuria (>10 RBC/hpf), and eGFR ≥15 mL/min/1.73 m2 (CKD-EPI formula) at inclusion (<1 month)
• Recent (<4 weeks) renal biopsy that confirms active renal involvement of ANCA-associated vasculitis
• Patients aged of 18 to 80 years
• Participant written informed consent prior to participation in the study
• Participants affiliated to a French health insurance system (registered or being a beneficiary of such a scheme)

Критерии исключения

• Alveolar haemorrhage requiring pulmonary ventilation support at inclusion
• Patients with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss)
• Active cancer (except non-melanoma skin cancer) within the past 24 months
• Active severe bacterial, viral or fungal infectious disease
• Past history of bladder or urinary tract cancer
• History of Class 3/4 congestive heart failure symptoms, any time
• History of Class 2 heart failure symptoms within the past 3 months and/or ejection fraction <40% on recent echocardiography (<1 month)
• Transaminases levels above 2 times the normal range value (<1 month) or any severe chronic liver disease
• Positive serology for HIV, HBV (Ag HBs positivity) or active HCV infection at inclusion
• Presence of neutropenia <1000 cells/l (<1 month)
• History of intolerance to any thiazolidinedione (including Pioglitazone), to rituximab or any excipient listed in SmPc
• Diabetic ketoacidosis, any time
• A pre-existing or an important risk of new-onset macular edema (confirmed by an ophthalmological examination)
• 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 (estrogen 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
• Severe neurologic or psychiatric disease (e.g., dementia or schizophrenia)
• Kidney transplant recipients
• Cyclophosphamide or rituximab (dose > 375 mg/m2) use within 26 weeks prior to screening; if on azathioprine, mycophenolate mofetil or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the first rituximab dose. Patients that have initiated induction therapy with rituximab for the actual flare, can be included in the present study within 48h following the first rituximab infusion
• Intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening
• Patients who have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to screening
• Current participation in another research study involving a therapeutic intervention. Participation to an observational research, or a non-interventional research is allowed
• Patients under guardianship or curators and protected adults
• Patients not able to understand and follow study procedures
• Patients on AME (Aide Médicale de l'Etat = State Medical Assistance)

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

Тройное слепое

Основная цель

Лечение

Центры проведения

Франция · 25 центров

• CHU Amiens — Amiens
• CHU d'Angers — Angers
• CH de Boulogne sur Mer — Boulogne-sur-Mer
• CHU Brest - Hôpital de la Cavale Blanche — Brest
• CHU de Dijon — Dijon
• CHU de Grenoble - Hôpital Michalon site nord — Grenoble
• Centre Hospitalier Départemental Vendée — La Roche-sur-Yon
• Hopital Le Kremlin Bicetre - Aphp — Le Kremlin-Bicêtre
• … и ещё 17 центров

Идентификаторы

NCT: NCT05946564 · APHP211045 · 2022-501057-36-00 · PHRC-20-0707

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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