EvER-ILD 2: Evaluation of Efficacy and safety of Rituximab in patients with progressive Interstitial Lung Disease (ILD) with inflammatory component: a multicentre double-blind placebo-controlled randomized trial

The primary objective of the EvER-ILD 2 study is to assess the **efficacy** of rituximab on lung function at 6 months compared to placebo in patients with progressive **interstitial lung disease** (ILD) with an inflammatory component. This evaluation is clinically relevant as it aims to determine the potential of rituximab to improve respiratory function in a condition characterized by progressive lung damage and inflammation, which can significantly impact patient morbidity and mortality.

Secondary objectives include:

• Evaluating the efficacy of rituximab treatment at 6 months versus placebo on progression-free survival, patient's quality of life, corticosteroid consumption, and various functional, radiographic, and biological parameters.
• Assessing the safety of rituximab compared to placebo throughout the study period.
• Evaluating adverse events in patients with anti-fibrosants at inclusion versus those without.
• Describing the evolution of SARS-COV2 antibodies from baseline to 6 months in the two randomization groups.
• Describing the pharmacokinetics of rituximab and the pharmacokinetic-pharmacodynamic relationship in these diseases.
• Identifying variables associated with the clinical response and potential adverse effects of rituximab.
• Establishing a collection of serum samples for further studies of potential new markers of treatment response in ILD patients.

The clinical trial involves participants diagnosed with **interstitial lung disease**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a progressive form of the disease with an inflammatory component, as evidenced by specific clinical criteria. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include a documented decline in lung function or worsening respiratory symptoms, alongside evidence of inflammation. Participants must be covered by the French social security system and provide written informed consent. The ability to comply with study requirements is also necessary. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **rituximab** in patients with progressive **interstitial lung disease** (ILD) with an inflammatory component. This study is a multicenter, double-blind, placebo-controlled, randomized trial. The trial aims to assess the change in lung function, specifically the Forced Vital Capacity (FVC), over a period of six months. Participants will be randomly assigned to receive either rituximab or a placebo, with both groups receiving two infusions over the course of the study. The trial is expected to last until April 2026, with recruitment having started in October 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age (≥18 years) and evidence of worsening ILD within the past 24 months. The presence of an inflammatory component, as indicated by histological patterns or alveolar lymphocytosis, is also required. Following the screening, participants will attend follow-up visits to monitor their health and the effects of the treatment. The primary endpoint is the change in FVC from baseline to six months, while secondary endpoints include progression-free survival, changes in quality of life questionnaires, and various biological markers.

The expected length of participant involvement is approximately six months, with conditions for early termination including significant adverse events or inability to comply with study requirements. Participants are required to provide written informed consent and must be covered by the French social security system. The study will also monitor adverse events, particularly serious infectious events, and assess pharmacokinetic parameters of rituximab. The trial's design ensures rigorous evaluation of rituximab's efficacy and safety in the target population, contributing valuable data to the understanding of treatment options for ILD with an inflammatory component.

The clinical trial involves the administration of **Rituximab**, an experimental medication, to evaluate its efficacy and safety in patients with progressive Interstitial Lung Disease (ILD) with an inflammatory component. Rituximab is administered in the form of a direct intravenous injection. The pharmaceutical form is designated as PHF00230MIG. The dosing regimen includes a maximum daily dose of 500 mg and a total maximum dose of 1000 mg over the treatment period. The treatment course consists of two infusions, administered over a maximum period of two weeks. Rituximab is classified under the ATC code L01XC02, indicating its role as a monoclonal antibody used in antineoplastic therapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to Rituximab, the trial utilizes a comparator treatment consisting of an infusion solution containing **Sodium Chloride** along with other active substances such as **Potassium Chloride**, **Sodium Hydrogen Carbonate**, and **Glucose Anhydrous**. This solution is also administered via direct intravenous injection, with a pharmaceutical form identified as PHF00169MIG. The maximum daily and total dose for this comparator treatment is 0.9% concentration. The comparator serves as a placebo to evaluate the efficacy of Rituximab against standard infusion solutions. The administration of the comparator follows the same schedule as the experimental treatment, ensuring a double-blind design. Compliance with the administration of the comparator is similarly monitored to maintain the integrity of the trial results.

The efficacy of rituximab in patients with progressive **Interstitial Lung Disease (ILD)** with an inflammatory component will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in Forced Vital Capacity (FVC) measured in milliliters from baseline to 6 months. This will provide a direct measure of lung function improvement or decline over the treatment period.

Secondary endpoints include a variety of measures to capture different aspects of disease progression and patient well-being. These include the change in FVC as a percentage of the predicted value, progression-free survival at 6 months, and changes in patient-reported outcomes using the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire and the L-PF symptom and impact questionnaire. Additionally, changes in the 6-minute walk test, accelerometer-assessed physical activity, and high-resolution computed tomography (HRCT) of chest images will be evaluated. Biological markers related to B-cell depletion, such as CD19 lymphocytes and gammaglobulins, will also be monitored, along with serology by ELISA of 15 environmental antigens.

Pharmacokinetic parameters of rituximab, including volume of distribution, clearance, and half-life, will be analyzed. The study will also track changes in SARS COV 2 antibodies and the cumulative doses of corticosteroids at 6 months. All adverse events, particularly serious infectious adverse events, will be documented throughout the six-month treatment period. These comprehensive assessments will be conducted at baseline and at the 6-month mark to determine the efficacy of rituximab in this patient population.