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

The primary objective of this multicenter randomized trial is to demonstrate a reduction of **renal damage** in patients with ANCA-associated vasculitis. This is assessed by the early improvement of proteinuria and serum creatinine levels, achieved through the addition of **pioglitazone** to the standard immunosuppressive regimen, which includes glucocorticoids and rituximab, over a period of six months. This objective is clinically relevant as it aims to enhance renal outcomes and potentially improve the long-term prognosis for patients with this condition.

Secondary objectives include:

• Evaluating the efficacy of pioglitazone in the long-term preservation of renal function.
• Measuring the impact of pioglitazone on renal and systemic vasculitis activity.
• Assessing the efficacy of pioglitazone in terms of quality of life improvements.
• Describing the clinical and biological tolerance of pioglitazone in the study population.
• Assessing the efficacy of pioglitazone in reducing hypertension and metabolic side effects associated with glucocorticoids.

The clinical trial involves participants diagnosed with **ANCA-associated vasculitis**, specifically granulomatosis with polyangiitis or microscopic polyangiitis. The study population includes both male and female subjects, aged between 18 to 80 years, who are in general good health aside from their condition. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including a recent renal biopsy confirming renal involvement, and the presence of proteinuria and haematuria. All participants are required to be affiliated with a French health insurance system. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **pioglitazone** in promoting renal tolerance in patients with **ANCA-associated vasculitis**. This is a multicenter, randomized, double-blind, controlled trial. The study will involve a total duration of 52 weeks, with participant involvement expected to last up to 26 weeks. The trial will include a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ANCA-associated vasculitis, and renal involvement. Participants will be randomly assigned to receive either pioglitazone or a placebo, in addition to a standardized immunosuppressive regimen including glucocorticoids and **rituximab**.

Study visits will occur at weeks 4, 12, 26, and 52, with assessments focusing on primary and secondary endpoints. The primary endpoint is the improvement of serum creatinine and urine protein-to-creatinine ratio at week 26. Secondary endpoints include renal function improvement, reduction of vasculitis activity, and quality of life assessments. Safety evaluations will be conducted to monitor adverse events and potential toxicity of pioglitazone. The end-of-study visit will occur at week 52, where final assessments will be made.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide valuable insights into the potential benefits of pioglitazone as an adjunct therapy in managing renal complications associated with ANCA-associated vasculitis.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in promoting renal tolerance in ANCA-associated vasculitis. The primary experimental medication is **Actos 30 mg tablets**, containing the active substance **pioglitazone**. This medication is administered orally with a maximum daily dose of 30 mg and a total dose of 5460 mg over a treatment period of 26 weeks. The role of pioglitazone in the trial is to assess its potential in reducing renal damage when used as an add-on treatment to the standard immunosuppressive regimen.

**Rituximab** is used as part of the standard-of-care therapy. It is provided as a solution for infusion, administered via intravenous infusion. The maximum daily dose is 375 mg/m², with a total dose of 375 mg/m² over a 6-week period. Rituximab is a protein-based medication, and its administration is monitored to ensure compliance with the dosing schedule.

**Methylprednisolone** is included in the trial as a powder for solution for injection, administered intravenously. The maximum daily dose is 100 mg, with a total dose of 600 mg over a 6-week period. Additionally, **methylprednisolone hemisuccinate** is used in a similar form and route, with a maximum daily dose of 15 mg/kg and a total dose of 15 mg/kg over a 3-week period. Both forms of methylprednisolone are chemical-based and are part of the immunosuppressive regimen.

**Prednisone** is administered orally in tablet form, with a maximum daily dose of 60 mg and a total dose of 21840 mg over a 52-week period. This chemical-based medication is also part of the standard immunosuppressive therapy.

**Dexchlorpheniramine** is provided as a solution for injection, administered intravenously. The maximum daily dose is 5 mg, with a total dose of 30 mg over a 6-week period. This medication is used as an auxiliary treatment in the trial.

**Paracetamol** is available in film-coated tablet form and can be administered orally or intravenously. The maximum daily dose is 1000 mg, with a total dose of 6000 mg over a 6-week period. Paracetamol serves as an auxiliary treatment to manage symptoms and ensure participant comfort.

A **placebo** of Actos 30 mg tablets is also utilized in the trial to maintain blinding and assess the efficacy of pioglitazone. The placebo is administered in a manner consistent with the active treatment to ensure the integrity of the trial results.

The efficacy of pioglitazone in promoting renal tolerance in patients with ANCA-associated vasculitis will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the improvement of renal function, specifically the reduction of serum creatinine levels by more than 30% from the inclusion value if the initial serum creatinine is greater than 135 µmol/L, and a urine protein-to-creatinine ratio (uPCR) of less than 1 g/g at week 26. A pre-specified subgroup analysis will be conducted based on age, renal pathology, initial renal function, de novo versus relapsing vasculitis, and ANCA specificity.

Secondary endpoints will evaluate various aspects of renal and systemic health at multiple timepoints, including weeks 4, 12, 26, and 52. These include the improvement of renal function as measured by changes in serum creatinine (Delta sCreat) and estimated glomerular filtration rate (eGFR), renal survival, and proteinuria levels. Renal survival will be determined by the percentage of patients alive and not requiring chronic dialysis. Proteinuria will be assessed using spot uPCR measurements. Systemic vasculitis activity will be evaluated using the Birmingham Vasculitis Activity Score (BVAS) and ANCA positivity, while residual renal vasculitis activity will be assessed through urine biomarkers such as microhematuria, MCP-1, KIM-1, Calprotectin, and CD163 levels.

Additional secondary endpoints include the assessment of quality of life using the Short Form-36 and EQ-5D-5L scales, safety of pioglitazone through monitoring adverse events and evaluating cardiac and liver toxicity via plasma BNP and liver enzyme levels, and the reduction of glucocorticoid-induced toxicity using the Glucocorticoid Toxicity Index (GTI). Metabolic effects of glucocorticoids will be evaluated by HbA1c levels and lipid profiles, while hypertension will be monitored through office measurements and ambulatory blood pressure monitoring (AMBP).