A multicenter randomized trial to evaluate the efficacy of pioglitazone to improve renal outcome in ANCA-associated vasculitis - RENATO

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

24 Oct 2023 → ongoing

Decision date (initial)

2023-04-17

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

French Ministry of Health (Hospital Funding for Clinical Research)

External identifiers

EU CT number

2022-501057-36-00

ClinicalTrials.gov

NCT05946564

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To demonstrate a reduction of renal damage (reflected by the early improvement of proteinuria and serum creatinine), in ANCA-associated renal vasculitis, by pioglitazone add-on treatment on top of Standard Of Care (SOC) standardized immunosuppressive regimen with glucocorticoids and rituximab, after six months

Secondary objectives 5

1. To evaluate the efficacy of pioglitazone add-on treatment on long-term preservation of renal function
2. To measure the impact of pioglitazone on renal and systemic vasculitis activity
3. To evaluate the efficacy of pioglitazone add-on treatment on in terms of quality of life
4. To describe the clinical and biological tolerance of pioglitazone in this population
5. To assess the efficacy of pioglitazone on the reduction of hypertension and metabolic side effects of glucocorticoids

Conditions and MedDRA coding

ANCA-associated vasculitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Newly-diagnosed or relapsing ANCA-associated vasculitis, i.e. granulomatosis with polyangiitis (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 vasculitis defined as a BVAS ≥ 3
2. Presence of proteinuria (uPCR >300 mg/g), haematuria (>10 RBC/hpf), and eGFR ≥15 mL/min/1.73 m² (CKD-EPI formula) at inclusion (<1month)
3. Recent (<4 weeks) renal biopsy that confirms renal involvement of ANCA-associated vasculitis
4. Patients aged of 18 to 80 years
5. Participant written informed consent prior to participation in the study
6. Participants affiliated to a French health insurance system (registered or being a beneficiary of such a scheme)

Exclusion criteria 23

1. Alveolar haemorrhage requiring pulmonary ventilation support at inclusion
2. Presence of neutropenia <1000 cells/µl (<1 month)
3. History of intolerance to any thiazolidinedione (including Pioglitazone), to rituximab or any excipient listed in SmPc
4. Diabetic ketoacidosis, any time
5. 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
6. Severe neurologic or psychiatric disease (e.g., dementia or schizophrenia)
7. Kidney transplant recipients
8. 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
9. Intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening
10. 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
11. Current participation in another research study involving a therapeutic intervention. Participation to an observational research, or a non-interventional research is allowed
12. Patients with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss
13. Patients under guardianship or curatorship and protected adults
14. Patients not able to understand and follow study procedures
15. Patients on AME (Aide Médicale de l’Etat = State Medical Assistance)
16. Active cancer (except non-melanoma skin cancer) within the past 24 months
17. Active severe bacterial, viral or fungal infectious disease
18. Past history of bladder or urinary tract cancer
19. History of Class 3/4 congestive heart failure symptoms, any time
20. History of Class 2 heart failure symptoms within the past 3 months and/or ejection fraction <40% on recent echocardiography (<1 month)
21. Transaminases levels above 2 times the normal range value (<1 month) or any severe chronic liver disease
22. Positive serology for HIV, HBV (Ag HBs positivity) or active HCV infection at inclusion
23. A pre-existing or an important risk of new-onset macular edema (confirmed by an ophthalmological examination)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Improvement of serum creatinine (Delta sCreat) >30% of inclusion value (if initial sCreat is >135 µmol/L) AND urine proteine-to-creatinine (uPCR) <1g/g, at week 26. A pre-specified subgroup analysis will be performed in patients according to age, renal pathology, initial renal function, de novo vs relapsing vasculitis and ANCA specificity.

Secondary endpoints 5

1. Improvement of renal function (Delta sCreat, eGFR), renal survival and proteinuria at weeks 4, 12, 26, 52: -Renal function evaluated by Delta sCreat (sCreat at inclusion-sCreat follow-up), sCreat slopes, eGFR modifications (CKD-Epi formula); -Renal survival evaluated as the % of patients still alive and not requiring chronic dialysis therapy; -Proteinuria measured by spot uPCR; -Reduction of systemic chronic damage due to vasculitis; -Vasculitis-associated damage assessed by VDI at weeks 26 & 52
2. Reduction of vasculitis activity at weeks 4, 12, 26, 52: -Residual activity of renal vasculitis evaluated by urine biomarkersme asurement: microhematuria, levels of urinary MCP-1, KIM-1, Calprotectin, CD163; -Systemic vasculitis activity assessed by the BVAS and by ANCA positivity; Percentage of patients with refractory vasculitis resistance and early vasculitis relapse at weeks 12, 26 & 52
3. Improvement of Quality of Life during follow-up, measured by Short Form-36 component and domain scores and the EQ-5D-5L visual analogue scale and index at week 4, 12, 26, 52
4. Safety of pioglitazone by evaluation of numbers of adverse events, number of patients with adverse events, numbers of serious adverse events, patient survival, at weeks 26 & 52. In addition, cardiac and liver toxicity of pioglitazone will be evaluated by assessment of plasma BNP and liver enzymes
5. Reduction of glucocorticoid-induced toxicity during follow-up: -Glucocorticoid-induced toxicity measured by GTI at weeks 12, 26 & 52 -Metabolic effects of glucocorticoids will be evaluated by HbA1c levels & evaluation of lipid profile (Total, HDL and LDL cholesterol, triglycerides) at weeks 12, 26 & 52; Reduction of nephropathy-induced hypertension and numbers of antihypertensive drugs given during follow-up; -Hypertension evaluated by office measurement at each study visit & AMBP at weeks 12&26

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Alexandre KARRAS

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Alexandre KARRAS

Locations

1 EU/EEA country · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications