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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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ANCA Associated Vasculitis, Rapidly Progressive Glomerulonephritis, Crescentic Glomerulonephritis

Intervention / Treatment
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* Drug: Pioglitazone (ACTOS®)
* Drug: Placebo of Pioglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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 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 HCV 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 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Comparative, multicentre, prospective, randomized, placebo-controlled double-blind phase III trial, evaluating the efficacy of add-on pioglitazone therapy on top of a standard of care (SOC) immunosuppressive therapy, in patients with ANCA-associated vasculitis and biopsy-proven renal involvement. Patients eligible for the study will be assigned in a 1:1 randomized fashion to additional treatment by pioglitazone (30 mg/day orally) or to placebo for 26 weeks on top of a SOC immunosuppressive treatment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone (ACTOS®)<br>Pioglitazone given once a day, orally, at 30 mg dose, for 26 weeks | Drug: Pioglitazone (ACTOS®)<br>* 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.<br>|
| Placebo Comparator: Placebo of pioglitazone<br>Placebo of pioglitazone, given once a day, orally, for 26 weeks | Drug: Placebo of Pioglitazone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Appearance of a success defined as (1) Delta sCreat > 30% (between D0 and week 26) AND (2) urine protein-to-creatinine (uPCR) < 1g/mmol |  | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of renal function | Delta sCreat (baseline sCreat - follow-up sCreat) | Weeks 4, 12, 26 and 52 | 
| Proteinuria ratio | Spot urine protein-to-creatinine ratio (uPCR) | Weeks 4, 12, 26 and 52 | 
| Score VDI (Vasculitis Damage Index) | Systemic chronic damage due to vasculitis and treatment of vasculitis Min : 0 Max : 62 the best score is 0 | Week 26 and 52 | 
| Renal vasculitis activity | measurement of urine biomarkers: MCP-1 | Weeks 4, 12, 26 and 52 | 
| Renal vasculitis activity | measurement of urine biomarkers: KIM-1 | Weeks 4, 12, 26 and 52 | 
| Renal vasculitis activity | measurement of urine biomarkers: Calprotectin | Weeks 4, 12, 26 and 52 | 
| Renal vasculitis activity | measurement of urine biomarkers: CD163 | Weeks 4, 12, 26 and 52 | 
| Systemic vasculitis activity : score BVAS | BVAS (Birmingham Vasculitis Activity Score ), ANCA positivity Min : 0 Max : 63 The best score is 0 | Weeks 4, 12, 26 and 52 | 
| Refractory vasculitis | Percentage of patients with refractory vasculitis and early vasculitis relapses | Weeks 12, 26 and 52 | 
| Improvement in Quality of Life (SF-36) | SF-36 : Short-form 36 Min : 0 Max : 100 A low score reflects a perception of poor health, loss of function, presence of pain. A high score reflects a perception of good health, an absence of functional deficit and pain. | baseline, weeks 4, 12, 26 and 52 | 
| Improvement in Quality of Life (EQ-5D) | EQ-5D : Euroqol Min: 0 Max : 100 Higher scores mean a better | baseline, weeks 4, 12, 26 and 52 | 
| Safety profile of pioglitazone | numbers of adverse events, numbers of patients with adverse events, numbers of serious adverse events | Weeks 26 and 52 | 
| Toxicity induced by glucocorticoids | Glucocorticoid Toxicity Index (GTI) the best score is 0 | Weeks 12, 26 and 52 | 
| Change metabolic effects of Glucocorticoids | To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by HbA1c | Weeks 12, 26 and 52. | 
| Change metabolic effects of Glucocorticoids | To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by evaluation of lipid profile | Weeks 12, 26 and 52. | 
| Change blood pressure | To assess the efficacy of pioglitazone on the reduction of hypertension) | Weeks 12 and 26. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ANCA, vasculitis