A Randomized, Double-Blind, Controlled Trial of Glucocorticoids and Rituximab Versus Glucocorticoids and Placebo in Adult IgA Vasculitis Patients

The primary objective of this study is to determine the efficacy of **rituximab** in inducing remission in patients with newly-diagnosed or relapsing adult IgA vasculitis (IgAV). This is clinically relevant as achieving remission is a critical goal in the management of IgAV, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Determining the duration of efficacy of a rituximab-based regimen to induce remission in these patients.
• Assessing the number of relapses.
• Comparing the safety profile of rituximab-based regimen and glucocorticoids alone at days 180 and 360.
• Measuring the glucocorticoids dose at days 180 and 360 and comparing the glucocorticoid sparing effect of rituximab.
• Assessing the proportion of patients in complete or partial renal remission at days 180 and 360.
• Evaluating renal outcomes.
• Comparing sequelae assessed by the Vasculitis Damage Index at days 180 and 360 in both arms.
• Comparing patient-reported outcomes (PRO) at days 180 and 360 after randomization in both arms, and during long-term follow-up.
• Comparing functional disability and quality of life at days 180 and 360 after randomization in both arms.
• Comparing the evolution of CD19+ cells in the two treatment groups, and assessing its correlation with clinical events during follow-up.

The clinical trial involves **participants** diagnosed with **IgA vasculitis (IgAV)**, as defined by the Chapel Hill Consensus Conference, with a requirement for a biopsy-proven diagnosis. The study population includes adults aged 18 years and older, encompassing both male and female subjects. Participants are either newly diagnosed or experiencing a relapse of the disease, with active manifestations attributable to IgAV and severe involvement of at least one organ. The trial does not include a vulnerable population. Participants must be within the first 21 days following the initiation or increase of corticosteroids at a dose of ≤1 mg/kg/day. The sponsor has not provided information regarding the total number of participants. All participants are required to have signed an informed consent form and be affiliated with national health insurance. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **rituximab** in combination with glucocorticoids compared to glucocorticoids plus placebo for inducing remission in patients with newly-diagnosed or relapsing IgA vasculitis (IgAV). This is a prospective, randomized, controlled, double-blind study. Participants will be randomly assigned in a 1:1 ratio to either the experimental group receiving rituximab and glucocorticoids or the control group receiving glucocorticoids and placebo. The trial is categorized as a Phase III, multicenter study, with a focus on superiority in treatment outcomes.

The trial is expected to last until March 15, 2025, with recruitment having started on March 15, 2022. Participants will be involved in the study for a maximum treatment period of 15 days, with follow-up assessments extending up to 360 days. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as a biopsy-proven diagnosis of IgAV, age of 18 years or older, and active disease status. Follow-up visits will occur at specified intervals to monitor disease remission, adverse events, and other health parameters. The end-of-study visit will assess the primary endpoint, which is the proportion of patients achieving remission with a prednisone dose of 0 mg/day at both days 180 and 360.

Participants may be withdrawn from the study if they experience severe adverse events, fail to adhere to the study protocol, or withdraw consent. The study aims to provide comprehensive data on the efficacy and safety of rituximab in treating IgAV, with secondary endpoints including remission rates at various time points, renal function parameters, and quality of life assessments. The trial's design ensures rigorous evaluation through its randomized, double-blind, and controlled methodology, contributing valuable insights into the management of IgAV.

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 concentrate that is prepared for intravenous infusion. The maximum daily dose is 1 gram, with a total treatment period not exceeding 15 days. The administration route is strictly intravenous, ensuring the direct delivery of the medication into the bloodstream. Participant compliance is monitored through scheduled dosing and infusion sessions, with adherence to the prescribed dosing schedule being critical for the trial's integrity.

Another experimental treatment in the trial is **Rixathon**, also a 500 mg concentrate for solution for infusion, containing **rituximab**. Similar to MabThera, Rixathon is administered intravenously, with a maximum daily dose of 1 gram and a treatment period of up to 15 days. The pharmaceutical form and administration route are consistent with standard practices for intravenous infusions, ensuring the medication's efficacy and safety are maintained throughout the trial.

The trial also includes a placebo control, consisting of a 0.9% NaCl solution (500 mL) administered via infusion. This placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment allocations. The placebo is administered in a manner identical to the active treatments, with the same infusion schedule and monitoring protocols to ensure consistency across all study arms.

All treatments, including the placebo, are administered under controlled conditions, with participant compliance being closely monitored through regular follow-ups and infusion records. The trial's design ensures that all participants receive the same level of care and monitoring, regardless of their treatment group, to maintain the study's scientific rigor and validity.

The efficacy of the clinical trial will be assessed by evaluating the ability of **rituximab** to induce remission in patients with newly-diagnosed or relapsing adult IgA vasculitis (IgAV). The primary endpoint for efficacy assessment is the proportion of patients alive who achieve remission with a prednisone dose of 0 mg/day at both days 180 and 360. Secondary endpoints include the proportion of patients in remission at days 180 and 360, the proportion of patients achieving remission for ≥3 consecutive months over the 360-day study period, and the proportion of patients with a Birmingham Vasculitis Activity Score (BVAS) of 0 or ≤5 if all scores were due to persistent hematuria or proteinuria, with a prednisone dose ≤5 mg/day at days 180 and 360.

Additional secondary endpoints involve renal parameters such as estimated glomerular filtration rate (eGFR), daily proteinuria, hematuria, arterial hypertension, and the use of angiotensin-converting enzyme inhibitors at days 180 and 360 compared with baseline. The trial will also assess prednisone dosage, area under the curve for prednisone dose, number of major and minor relapses, cumulative incidence of relapse, and time to first IgAV relapse. Adverse events will be recorded according to the CTCAE toxicity grading system, and quality of life will be measured using the HAQ and SF-36 questionnaires. Patient-reported outcomes, including disease activity, anxiety, depression, and treatment adherence, will be evaluated at days 180 and 360, as well as during long-term follow-up. The Vasculitis Damage Index and patient survival will also be assessed at these timepoints.