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

Inclusion Criteria:

• Newly-diagnosed or relapsing ANCA-associated vasculitis, i.e. granulomatosis withpolyangitis (GPA) or microscopic polyangiitis (MPA), according to ACR 1990 criteriaand/or revised Chapel Hill Consensus Conference definitions and/or European MedicalAgency algorithm, with an active disease defined as a BVAS ≥3

• Presence of proteinuria (UPCR >300 mg/g), haematuria (>10 RBC/hpf), and eGFR ≥15mL/min/1.73 m2 (CKD-EPI formula) at inclusion (<1 month)

• Recent (<4 weeks) renal biopsy that confirms active renal involvement ofANCA-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 abeneficiary of such a scheme)

Exclusion Criteria:

• 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 ejectionfraction <40% on recent echocardiography (<1 month)

• Transaminases levels above 2 times the normal range value (<1 month) or any severechronic liver disease

• Positive serology for HIV, HBV (Ag HBs positivity) or active HCV infection atinclusion

• Presence of neutropenia <1000 cells/l (<1 month)

• History of intolerance to any thiazolidinedione (including Pioglitazone), torituximab or any excipient listed in SmPc

• Diabetic ketoacidosis, any time

• A pre-existing or an important risk of new-onset macular edema (confirmed by anophthalmological examination)

• Pregnant or breast-feeding women, or desire to become pregnant within 24 months Allwomen of childbearing potential (WOCBP) are required to have a negative pregnancytest before treatment and must agree to maintain highly effective contraception bypracticing abstinence or by using an effective method of birth control from the dateof consent through the end of the study and another 12 months after (or 12 monthsafter the last rituximab infusion in case of premature termination): Combined (estrogen and progestogen containing) hormonal contraception associated withinhibition of ovulation (Oral, Intravaginal, Transdermal); Progestogen-only hormonalcontraception 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 toscreening; if on azathioprine, mycophenolate mofetil or methotrexate at the time ofscreening, these drugs must be withdrawn prior to receiving the first rituximabdose. Patients that have initiated induction therapy with rituximab for the actualflare, can be included in the present study within 48h following the first rituximabinfusion

• Intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeksprior to screening

• Patients who have been taking an oral daily dose of a glucocorticoid of more than 10mg prednisone-equivalent for more than 6 weeks continuously prior to screening

• Current participation in another research study involving a therapeuticintervention. Participation to an observational research, or a non-interventionalresearch 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)