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

Study Overview
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Brief Summary
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The main objective of the EvER-ILD2 study is to evaluate the efficacy on lung function at 6 months of one course rituximab (2 infusions) comparatively to one course of placebo (2 infusions) in a broad range of progressive ILD patients with inflammatory component.

Official Title
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Evaluation de l'efficacité et de la sécurité du Rituximab Chez Les Patients Avec Une Pneumopathie Interstitielle Diffuse Progressive Avec Composante Inflammatoire : Essai Clinique randomisé Multicentrique en Double Insu Contre Placebo

Conditions
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Lung Diseases

Intervention / Treatment
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* Drug: Rituximab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years old Who meet at least one of the following criteria for worsening ILD within 24 months: a relative decline in the FVC of >= 10% of the predicted value a relative decrease in the FVC of >=5 to 10% of the predicted value AND i) worsening respiratory symptoms OR ii) an increased extent of ILD on high-resolution CT OR iii) a relative decrease in the DLCO of >= 15% of the predicted value. worsening of respiratory symptoms AND an increased extent of ILD on high-resolution CT AND presence of an inflammatory component defined by a previous histological pattern with lymphocyte infiltrations distant from pulmonary fibrosis to suggest an inflammatory component on pulmonary sample (for example: interstitial lymphoid aggregates with germinal centers, diffuse lympho-plasmocytic infiltrations, granulomas, giant cells or centrilobular inflammation…) OR a previous alveolar lymphocytosis >20% on Bronchoalveolar lavage fluid (BALF) Subjects covered by the French social security system Written informed consent obtained from subject Ability for subject to comply with the requirements of the study Exclusion Criteria: Known diagnosis of significant respiratory disorders (asthma, tuberculosis, aspergillosis, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), Connective Tissue Diseases-ILD, sarcoidosis, desquamative interstitial pneumonia, pulmonary hypertension (PAMp > 30mmHg))) or of significant severe heart failure. Concomitant medical or surgical disease, clinically significant as considered by the investigator, serious or unstable, acute or chronically progressive, or any condition that could affect the safety of the patient, in the opinion of the investigator including cardiomyopathy or heart failure. Patient who can not walk more than 100 meters at 6-minutes walk test HRCT profile of typical usual interstitial pneumonia (UIP) Histological model of typical NSIP or definitive UIP Initiation of a new therapy or with interruption/modification of therapy dosage within 6 weeks prior to visit 1 Patient who has already received a rituximab-based treatment line Known hypersensitivity to rituximab, to murine proteins or other excipients or sulfonamide antibiotics. Treatment with monoclonal antibodies (such as, but not limited to, etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab) within 6 months (if 5 half-lives ≤ 6 months) prior to inclusion. Patients on a lung transplant list Pregnant or breastfeeding women, or women of childbearing age not using a reliable method of contraception during the study and for 12 months following the end of the study treatment. Patients at high risk of infectious complications: Human Immunodeficiency Virus (HIV) positive or other known immunodeficiency syndromes, hepatitis B and C (HBV, HCV), coronavirus disease (within 3 month) or other known viral infection, infection requiring anti-infective treatment within 4 weeks of inclusion. Patients with incomplete anti-severe acute respiratory syndrome coronavirus 2 vaccine regimen (according to current recommendations) and in this case who has not receive a treatment with therapeutic antibodies anti-SARSCov2 (ex: tixagévimab/cilgavimab) Patient under judicial protection, deprivation of liberty Participation in other interventional research with an investigational drug or medical device.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br> | Drug: Rituximab<br>* One course of IV rituximab consisting of a first infusion of 1000 mg (500 mL solution) rituximab (day 1), and a second infusion of 1000 mg (500 mL solution) rituximab two weeks later (day 15)<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* One course of IV placebo of rituximab consisting of a first infusion of 500 mL of saline (0.9% sodium chloride) infusion (day 1), and a second infusion of 500 mL of saline infusion two weeks later (day 15)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced vital capacity | The primary outcome is the change in Forced Vital Capacity (FVC) (in mL) from baseline to 6 months. | From baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced vital capacity | Change from baseline to 6 months in FVC (in % of predicted) | From baseline to 6 months | 
| Progression free survival (PFS) | Progression free survival (PFS) defined as the time to (first event considered): a first acute exacerbation, or a relative decline in the FVC of ≥ 10% of the predicted value or the need for new immunosuppressive or/and anti-fibrotic therapies (excluding corticosteroids), or inclusion on a lung transplant list, or death. | At 6 months | 
| King's Brief Interstitial Lung Disease (K-BILD) questionnaire | Changes in the King's Brief Interstitial Lung Disease (K-BILD) questionnaire.13 questions about the impact of lung disease on life. | From baseline to 6 months | 
| L-PF symptom questionnaire | Changes in Living Pulmonary fibrosis-symptom questionnaire.23 questions about the impact of lung disease on life. | From baseline to 6 months | 
| L-PF impact questionnaire | Changes in Living Pulmonary fibrosis-impact questionnaire.21 questions about the impact of lung disease on life. | From baseline to 6 months | 
| Cumulative doses of corticosteroids | Difference in cumulative doses of corticosteroids | At 6 months | 
| Diffusing capacity for carbon monoxide (DLCO) | Changes in % of predicted diffusing capacity for carbon monoxide (DLCO) | From baseline to 6 months | 
| 6 minutes walk test | Changes in the 6-minute walk test | From baseline to 6 months | 
| Accelerometer-assessed physical activity | Change in accelerometer-assessed physical activity | From baseline to 6 months | 
| Biological analyse on markers related to B-cell depletion | Changes of biological markers related to B-cell depletion | From baseline to 6 months | 
| Environmental antigens | Changes of serology by ELISA of 15 environmental antigens. | From baseline to 6 months | 
| High-resolution computed tomography (HRCT) of chest images | Changes in high-resolution computed tomography (HRCT) of chest images | From baseline to 6 months | 
| Adverse events | Description of All adverse events, especially serious infectious adverse events, occurring during the six-month treatment period | From baseline to 6 months | 
| Pharmacokinetic parameters of rituximab | Rituximab clearance | before and 2 hours after the end of each infusions, at 3 and 6 months after the first infusion | 
| Pharmacokinetic parameters of rituximab | Volume of distribution | Before and 2 hours after the end of each infusions, at 3 and 6 months after the first infusion | 
| Pharmacokinetic parameters of rituximab | Half life | Before and 2 hours after the end of each infusions, at 3 and 6 months after the first infusion | 
| Severe Acute Respiratory Syndrome COronaVirus 2 (SARS COV 2) antibodies | Change of SARS COV 2 antibodies | From baseline to 6 months |