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 (EvER-ILD2)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Lung Diseases
• Intervention / Treatment: Drug: Rituximab; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sylvain MARCHAND ADAM, PhD; Phone Number: +33 2 47 47 98 34; Email: sylvain.marchand-adam@univ-tours.fr

Study Locations

• France
  • Tours, France
    • Recruiting
    • CHRU Tours
    • Contact: Sylvain MARCHAND-ADAM

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients ≥ 18 years old

2. Who meet at least one of the following criteria for worsening ILD within 24 months:

   1. a relative decline in the FVC of >= 10% of the predicted value
   2. 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.
   3. worsening of respiratory symptoms AND an increased extent of ILD on high-resolution CT

3. AND presence of an inflammatory component defined by

   1. 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…)
   2. OR a previous alveolar lymphocytosis >20% on Bronchoalveolar lavage fluid (BALF)
4. Subjects covered by the French social security system
5. Written informed consent obtained from subject
6. Ability for subject to comply with the requirements of the study

Exclusion Criteria:

1. 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.
2. 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.
3. Patient who can not walk more than 100 meters at 6-minutes walk test
4. HRCT profile of typical usual interstitial pneumonia (UIP)
5. Histological model of typical NSIP or definitive UIP
6. Initiation of a new therapy or with interruption/modification of therapy dosage within 6 weeks prior to visit 1
7. Patient who has already received a rituximab-based treatment line
8. Known hypersensitivity to rituximab, to murine proteins or other excipients or sulfonamide antibiotics.
9. 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.
10. Patients on a lung transplant list
11. 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.
12. 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.
13. 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)
14. Patient under judicial protection, deprivation of liberty
15. Participation in other interventional research with an investigational drug or medical device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; 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)
Experimental: Rituximab	Drug: Rituximab; 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)

What is the study measuring?

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
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
King's Brief Interstitial Lung Disease (K-BILD) questionnaire	Changes in the King's Brief Interstitial Lung Disease (K-BILD) questionnaire.15 questions about the impact of lung disease on life.	From baseline to 6 months

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Study Director: Julien LE BONNIEC, University Hospital Center of Tours

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2023
• Primary Completion (Estimated): July 16, 2026
• Study Completion (Estimated): July 16, 2026

Study Registration Dates

• First Submitted: October 19, 2022
• First Submitted That Met QC Criteria: October 24, 2022
• First Posted (Actual): October 27, 2022

Study Record Updates

• Last Update Posted (Actual): July 24, 2024
• Last Update Submitted That Met QC Criteria: July 22, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: DR210299

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No