search
Back to results

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

Primary Purpose

ANCA Associated Vasculitis, Rapidly Progressive Glomerulonephritis, Crescentic Glomerulonephritis

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Pioglitazone (ACTOS®)
Placebo of Pioglitazone
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ANCA Associated Vasculitis focused on measuring ANCA, vasculitis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Pioglitazone (ACTOS®)

    Placebo of pioglitazone

    Arm Description

    Pioglitazone given once a day, orally, at 30 mg dose, for 26 weeks

    Placebo of pioglitazone, given once a day, orally, for 26 weeks

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Change of renal function
    Delta sCreat (baseline sCreat - follow-up sCreat)
    Proteinuria ratio
    Spot urine protein-to-creatinine ratio (uPCR)
    Score VDI (Vasculitis Damage Index)
    Systemic chronic damage due to vasculitis and treatment of vasculitis Min : 0 Max : 62 the best score is 0
    Renal vasculitis activity
    measurement of urine biomarkers: MCP-1
    Renal vasculitis activity
    measurement of urine biomarkers: KIM-1
    Renal vasculitis activity
    measurement of urine biomarkers: Calprotectin
    Renal vasculitis activity
    measurement of urine biomarkers: CD163
    Systemic vasculitis activity : score BVAS
    BVAS (Birmingham Vasculitis Activity Score ), ANCA positivity Min : 0 Max : 63 The best score is 0
    Refractory vasculitis
    Percentage of patients with refractory vasculitis and early vasculitis relapses
    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.
    Improvement in Quality of Life (EQ-5D)
    EQ-5D : Euroqol Min: 0 Max : 100 Higher scores mean a better
    Safety profile of pioglitazone
    numbers of adverse events, numbers of patients with adverse events, numbers of serious adverse events
    Toxicity induced by glucocorticoids
    Glucocorticoid Toxicity Index (GTI) the best score is 0
    Change metabolic effects of Glucocorticoids
    To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by HbA1c
    Change metabolic effects of Glucocorticoids
    To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by evaluation of lipid profile
    Change blood pressure
    To assess the efficacy of pioglitazone on the reduction of hypertension)

    Full Information

    First Posted
    June 6, 2023
    Last Updated
    July 7, 2023
    Sponsor
    Assistance Publique - Hôpitaux de Paris
    Collaborators
    Ministry of Health, France
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT05946564
    Brief Title
    A Trial to Evaluate the Efficacy of Pioglitazone to Promote Renal Tolerance in ANCA-associated Vasculitis - RENATO Trial
    Acronym
    RENATO
    Official Title
    A Multicenter Randomized Trial to Evaluate the Efficacy of Pioglitazone to Promote Renal Tolerance in ANCA-associated Vasculitis - RENATO
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    July 2023 (Anticipated)
    Primary Completion Date
    December 2, 2025 (Anticipated)
    Study Completion Date
    June 2, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Assistance Publique - Hôpitaux de Paris
    Collaborators
    Ministry of Health, France

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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
    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    ANCA Associated Vasculitis, Rapidly Progressive Glomerulonephritis, Crescentic Glomerulonephritis
    Keywords
    ANCA, vasculitis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    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
    ParticipantInvestigatorOutcomes Assessor
    Masking Description
    Double-blind (investigators and patients)
    Allocation
    Randomized
    Enrollment
    126 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Pioglitazone (ACTOS®)
    Arm Type
    Experimental
    Arm Description
    Pioglitazone given once a day, orally, at 30 mg dose, for 26 weeks
    Arm Title
    Placebo of pioglitazone
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo of pioglitazone, given once a day, orally, for 26 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    Pioglitazone (ACTOS®)
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo of Pioglitazone
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Appearance of a success defined as (1) Delta sCreat > 30% (between D0 and week 26) AND (2) urine protein-to-creatinine (uPCR) < 1g/mmol
    Time Frame
    Week 26
    Secondary Outcome Measure Information:
    Title
    Change of renal function
    Description
    Delta sCreat (baseline sCreat - follow-up sCreat)
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Proteinuria ratio
    Description
    Spot urine protein-to-creatinine ratio (uPCR)
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Score VDI (Vasculitis Damage Index)
    Description
    Systemic chronic damage due to vasculitis and treatment of vasculitis Min : 0 Max : 62 the best score is 0
    Time Frame
    Week 26 and 52
    Title
    Renal vasculitis activity
    Description
    measurement of urine biomarkers: MCP-1
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Renal vasculitis activity
    Description
    measurement of urine biomarkers: KIM-1
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Renal vasculitis activity
    Description
    measurement of urine biomarkers: Calprotectin
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Renal vasculitis activity
    Description
    measurement of urine biomarkers: CD163
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Systemic vasculitis activity : score BVAS
    Description
    BVAS (Birmingham Vasculitis Activity Score ), ANCA positivity Min : 0 Max : 63 The best score is 0
    Time Frame
    Weeks 4, 12, 26 and 52
    Title
    Refractory vasculitis
    Description
    Percentage of patients with refractory vasculitis and early vasculitis relapses
    Time Frame
    Weeks 12, 26 and 52
    Title
    Improvement in Quality of Life (SF-36)
    Description
    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.
    Time Frame
    baseline, weeks 4, 12, 26 and 52
    Title
    Improvement in Quality of Life (EQ-5D)
    Description
    EQ-5D : Euroqol Min: 0 Max : 100 Higher scores mean a better
    Time Frame
    baseline, weeks 4, 12, 26 and 52
    Title
    Safety profile of pioglitazone
    Description
    numbers of adverse events, numbers of patients with adverse events, numbers of serious adverse events
    Time Frame
    Weeks 26 and 52
    Title
    Toxicity induced by glucocorticoids
    Description
    Glucocorticoid Toxicity Index (GTI) the best score is 0
    Time Frame
    Weeks 12, 26 and 52
    Title
    Change metabolic effects of Glucocorticoids
    Description
    To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by HbA1c
    Time Frame
    Weeks 12, 26 and 52.
    Title
    Change metabolic effects of Glucocorticoids
    Description
    To assess the efficacy of pioglitazone on the reduction metabolic side effects of glucocorticoids by evaluation of lipid profile
    Time Frame
    Weeks 12, 26 and 52.
    Title
    Change blood pressure
    Description
    To assess the efficacy of pioglitazone on the reduction of hypertension)
    Time Frame
    Weeks 12 and 26.

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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)
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Ophélie Rogier
    Phone
    01 44 84 17 89
    Email
    ophelie.rogier@aphp.fr
    First Name & Middle Initial & Last Name or Official Title & Degree
    Laura Le Mao
    Phone
    01 56 09 54 97
    Email
    laura.le-mao@aphp.fr
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Alexandre Karras
    Organizational Affiliation
    Assistance Publique - Hôpitaux de Paris
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared
    IPD Sharing Time Frame
    Two years after the last publication
    IPD Sharing Access Criteria
    Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered. Data sharing must respect the agreements made with funders. Teams wishing obtain IPD must meet the sponsor and IP team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractual agreement. Processing of shared data must comply with European General Data Protection Regulation (GDPR).

    Learn more about this trial

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

    We'll reach out to this number within 24 hrs