Evaluation of Remission Maintenance with Extended Prednisone Administration in ANCA-Associated Vasculitis Using Rituximab Therapy

The primary objective of the study is to evaluate the **relapse rate** of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who continue low-dose **prednisone** treatment until 13 months, compared to those who cease prednisone treatment after one month. This is assessed in the context of remission maintenance with **rituximab** therapy, with remission defined as maintaining a Birmingham Vasculitis Activity Score (BVAS) of 0 at Month 30. This objective is clinically relevant as it aims to determine the optimal duration of prednisone therapy to maintain remission in patients with ANCA-associated vasculitis, potentially impacting long-term treatment strategies and patient outcomes.

Secondary objectives include: - Comparing the rate of adverse events (AE) and serious adverse events (SAE) between Day 1 and Month 30. - Comparing the rate of predefined severe events related to glucocorticoids, such as osteoporotic fractures and weight gain, between Day 1 and Month 30. - Comparing the duration of complete remission, defined as the total accrued duration in weeks with BVAS=0, between Day 1 and Month 30. - Comparing the rate of minor and major vasculitis relapse at Month 30. - Comparing the side effects related to low-dose prednisone using the GTI toxicity scale between Day 1 and Month 30. - Comparing prednisone use between Day 1 and Month 30. - Comparing the number of deaths between Day 1 and Month 30.

The clinical trial involves **patients** in remission for **granulomatosis with polyangiitis** (GPA) or microscopic polyangiitis (MPA), achieved with rituximab, cyclophosphamide, or methotrexate. The study population includes both male and female participants aged 18 years or older. Participants are required to be in remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0, and must have received glucocorticoids for a specified duration following diagnosis or last flare. At the inclusion visit, patients must be on a prednisone dosage between 5 and 10 mg/day, and at randomization, they must be at 5 mg/day. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include patients who have given informed consent and meet the American College of Rheumatology 1990 criteria and/or the revised Chapel Hill Consensus Conference definition for MPA or GPA, regardless of ANCA status. Participants have also received a 500 mg low-dose rituximab maintenance infusion at remission achievement, according to the MAINRITSAN and MAINRITSAN3 trials.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy of extended administration of **prednisone** in maintaining remission in patients with **granulomatosis with polyangiitis** (GPA) or **microscopic polyangiitis** (MPA). The trial will involve participants who have achieved remission with **rituximab**, **cyclophosphamide**, or **methotrexate**. The primary objective is to assess the relapse rate of patients continuing low-dose prednisone treatment until 13 months versus those who cease prednisone after one month, with remission maintenance supported by rituximab therapy. The trial is expected to last until October 2028, with participant involvement spanning approximately 30 months from the start of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and current remission status. At the randomization visit (Day 1), participants will be assigned to either the treatment or placebo group. Follow-up visits will occur at regular intervals to monitor health status, medication adherence, and any adverse events. The end-of-study visit will take place at Month 30, where the primary endpoint of relapse-free survival will be evaluated. Secondary endpoints include the proportion of patients experiencing adverse events, vasculitis flares, and changes in bone mineral density.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, non-compliance with study protocols, or withdrawal of consent. The study aims to provide valuable insights into the long-term management of GPA and MPA, contributing to improved therapeutic strategies for these conditions.

The clinical trial involves the administration of **MabThera**, a 500 mg concentrate for solution for infusion, containing the active substance **rituximab**. This pharmaceutical form is a solution for infusion, administered via **intravenous perfusion use**. The maximum daily dose is 500 mg, with a total maximum dose of 1500 mg over a treatment period of up to 12 months. Rituximab is a protein-based therapeutic agent, specifically classified under the ATC code L01XC02. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to the experimental treatment, the study includes the administration of **CORTANCYL**, a 1 mg tablet containing the active substance **prednisone**. This medication is administered orally, with a maximum daily dose of 5 mg and a total maximum dose of 1900 mg over a treatment period of up to 13 months. Prednisone is a chemically derived substance, classified under the ATC code H02AB07. The dosing schedule is designed to evaluate the maintenance of remission in patients with ANCA-associated vasculitis.

The trial also utilizes **microcrystalline cellulose** as a placebo, presented in a film-coated tablet form. This placebo is administered orally, with a maximum daily dose of 5 mg and a total maximum dose of 1900 mg over a treatment period of up to 13 months. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased assessment of the experimental treatment's efficacy. Compliance with the placebo administration is monitored to maintain the integrity of the trial results.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **relapse-free survival** at Month 30, which is 18 months after the last rituximab maintenance infusion. A relapse is defined as a Birmingham Vasculitis Activity Score (BVAS) greater than 0. Secondary endpoints include the proportion of patients experiencing at least one adverse event (AE) between Day 1 and Month 30, the percentage of patients with at least one minor or major vasculitis flare or a predefined severe event, and the percentage of patients with at least one serious adverse event (SAE) during the same period. Additionally, the trial will measure the percentage of patients with minor or major vasculitis and the time to first vasculitis relapse, variation in GTI toxicity score, prednisone area under the curve of administrated dose, number of deaths, and variation in bone mineral density from Day 1 to Month 30.