Evaluation of Efficacy and Safety of Rituximab With Mycophenolate Mofetil in Patients With Interstitial Lung Diseases

NCT02990286 | Completed Phase 3 DMC

• 1 other identifier: PHRN15-SMA/EvER-ILD
• Study Type: interventional
• Target: 122
• Locations: 1 country
• Sites: 5

Brief Summary

The purpose of the study is to evaluate the efficacy on lung function 6 months after one course of rituximab (2 infusions) and mycophénolate mofétil (MMF) treatment compared to one course of placebo and 6 months of MMF treatment in a broad range of patients with Interstitial Lung Diseases (ILD) non-responders to a first line immunosuppressive treatment.

Conditions

Lung Disease, Interstitial

Keywords

Non specific intertitial pneumonia; interstitial pneumonia with autoimmune feature; connective tissue disease; rituximab; Mycophenolate Mofetil; pulmonary fibrosis

Outcome Measures

Primary Outcomes (1)

• Change in FVC in % of predicted

  Change in FVC (in % of predicted) since declines in FVC correlates with increased risk of subsequent mortality in ILD patients and FVC is one of the core set of outcomes defined in interstitial lung diseases. Data obtained from the two groups of patients (rituximab and placebo) will be compared to each other. FVC will be performed in each study center in a standardized manner according to the ATS/ERS recommendations and ECCS reference equations

  From baseline to 6 months

Secondary Outcomes (16)

• Progression Free Survival (PFS).

  PFS measured at 3, 6 and 12 months

• Changes in the quality of life score

  Changes from baseline to 6 months in the quality of life score, and, changes from baseline to 6 months in the visual analogic scales of dyspnea and cough

• Changes in the visual analogic scales of dyspnea

  Changes from baseline to 6 months in the quality of life score, and, changes from baseline to 6 months in the visual analogic scales of dyspnea and cough

• Cough evaluation

  Changes from baseline to 6 months in cough evaluation

• Cumulative doses of corticoids for the 2 groups

  Cumulative doses of corticoids at 6 months

Study Arms (2)

Rituximab with Mycophenolate Mofetil

EXPERIMENTAL

Drug: Rituximab; Drug: Mycophenolate Mofetil

Placebo of rituximab with Mycophenolate Mofetil

PLACEBO COMPARATOR

Drug: Placebo of Rituximab; Drug: Mycophenolate Mofetil

Interventions

Rituximab DRUG

Rituximab 500mg concentrate for solution for infusion. One course of IV rituximab consisting of a first infusion of 1000 mg (500 ml solution) rituximab (day 1 infusion), and a second infusion of 1000 mg (500 ml solution) rituximab two weeks later (day 15 infusion)

Rituximab with Mycophenolate Mofetil

Placebo of Rituximab DRUG

500 ml of saline (0.9% sodium chloride) for infusion One course of intravenous placebo of rituximab consisting of a first infusion of 500 ml of saline (0.9% sodium chloride) infusion (day 1 infusion), and a second infusion of 500 ml of saline infusion two weeks later (day 15 infusion)

Placebo of rituximab with Mycophenolate Mofetil

Mycophenolate Mofetil DRUG

Mycophenolate Mofetil 500mg film-coated tablets 1 gram twice daily on oral route of MMF (= 2 grams daily) for 6 months.

Placebo of rituximab with Mycophenolate Mofetil; Rituximab with Mycophenolate Mofetil

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• A diagnosis of ILD:
• ILD associated with differentiated CTD or IPAF (based on internationally accepted criteria)
• OR idiopathic ILD
• A diagnosis of NSIP based on:
• a histological pattern of NSIP
• OR HRCT findings suggestive of NSIP defined as basal predominant reticular abnormalities with traction bronchiectasis, peri-bronchovascular extension and subpleural sparing, frequently associated with ground-glass attenuation
• Patients who did not respond or relapsed or were not able to continue at least one first-line immunosuppressive treatment of ILD: corticosteroids, azathioprine, cyclophosphamide or other immunosuppressants. For the assessment of clinical response, the absence of response was defined as: either a decrease or an increase, but \<10% in % predicted FVC.
• Subjects covered by or having the rights to French social security (including CMU),
• Written informed consent obtained from subject, with a specific check box on the Consent form of the study, understanding the risk for men and women treated with mycophenolate mofetil. And additional written consent from subject on the care and contraception agreement form for women of childbearing potential treated with mycophenolate.
• Ability for subject to comply with the requirements of the study

You may not qualify if:

• Known diagnosis of significant respiratory disorders (asthma, tuberculosis, sarcoidosis, aspergillosis, or cystic fibrosis) other than CTD-NSIP, IPAF-NSIP and iNSIP
• Evidence of any clinically significant, severe or unstable, acute or chronically progressive cardiac (severe heart failure New York Heart Association Class IV or severe uncontrolled cardiac disease), other medical disease (other than NSIP) or surgical disorder, or any condition that may affect patient safety in the judgment of the investigator.
• HRCT pattern of typical usual interstitial pneumonia (UIP)
• For patients with idiopathic ILD, HRCT pattern of possible UIP (no evocative of NSIP)
• Histological pattern other than pattern of NSIP
• A first line treatment with MMF or rituximab
• Known hypersensitivity to MMF or rituximab or sulfonamide antibiotics
• Treatment with immunosuppressive treatments other than corticosteroids:
• Patients registered on a pulmonary transplantation list
• Patients with known hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) hereditary deficiency (such as Lesch-Nyhan and Kelley-Seegmiller syndrome)
• Pregnant or breastfeeding women, or women of child-bearing potential not using two reliable contraceptive methods (including female partners of sexually active men treated with mycophenolate) and men not using a contraceptive method (condom), or women and men having a pregnancy project during the year following randomization.
• Patients at significant risk for infectious complications: HIV positive, other known immunodeficiency syndromes, untreated tuberculosis, hepatitis B and C or other known viral infection, infection requiring anti-infectious treatment in the preceding 4 weeks
• Current history of substance and/or alcohol abuse
• Deprivation of liberty, under judicial protection
• Participation in another biomedical research with experimental drug or medical device

Sponsors & Collaborators

• University Hospital, Tours: lead

Study Sites (5)

Chu Besancon

Besançon, 25030, France

Location

Chu Dijon

Dijon, 21079, France

Location

AP-HM Hôpital NORD

Marseille, 13015, France

Location

Chu Rennes

Rennes, 35033, France

Location

CHRU Tours

Tours, 37044, France

Location

Related Publications (2)

• Mankikian J, Caille A, Reynaud-Gaubert M, Agier MS, Bermudez J, Bonniaud P, Borie R, Brillet PY, Cadranel J, Court-Fortune I, Crestani B, Debray MP, Gomez E, Gondouin A, Hirschi-Santelmo S, Israel-Biet D, Jouneau S, Juvin K, Leger J, Kerjouan M, Marquette CH, Naccache JM, Nunes H, Plantier L, Prevot G, Quetant S, Traclet J, Valentin V, Uzunhan Y, Wemeau-Stervinou L, Bejan-Angoulvant T, Cottin V, Marchand-Adam S; EVER-ILD investigators and the OrphaLung network. Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2023 Jun 8;61(6):2202071. doi: 10.1183/13993003.02071-2022. Print 2023 Jun.

  PMID: 37230499 RESULT

• Bejan-Angoulvant T, Naccache JM, Caille A, Borie R, Nunes H, Ferreira M, Cadranel J, Crestani B, Cottin V, Marchand-Adam S; OrphaLung. Evaluation of efficacy and safety of rituximab in combination with mycophenolate mofetil in patients with nonspecific interstitial pneumonia non-responding to a first-line immunosuppressive treatment (EVER-ILD): A double-blind placebo-controlled randomized trial. Respir Med Res. 2020 Nov;78:100770. doi: 10.1016/j.resmer.2020.100770. Epub 2020 May 23.

  PMID: 32777737 DERIVED

MeSH Terms

Conditions

Lung Diseases, Interstitial; Connective Tissue Diseases; Pulmonary Fibrosis

Interventions

Rituximab; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Skin and Connective Tissue Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Study Officials

• TRACLET Julie

  HC LYON

  PRINCIPAL INVESTIGATOR

• NUNES Hilario

  AP-HP - Hôpital Avicenne

  PRINCIPAL INVESTIGATOR

• CRESTANI Bruno

  AP-HP - Hôpital Bichat

  PRINCIPAL INVESTIGATOR

• ISRAEL BIET Dominique

  AP-HP HEGP

  PRINCIPAL INVESTIGATOR

• NACCACHE Jean-Marc

  AP-HP - Hôpital Tenon

  PRINCIPAL INVESTIGATOR

• WEMEAU Lidwine

  CHRU LILLE

  PRINCIPAL INVESTIGATOR

• JOUNEAU Stéphane

  CHU Rennes

  PRINCIPAL INVESTIGATOR

• PREVOT Grégoire

  University Hospital, Toulouse

  PRINCIPAL INVESTIGATOR

• REYNAUD-GAUBERT Martine

  AP-HM Hôpital Nord

  PRINCIPAL INVESTIGATOR

• HIRSCHI SANTELMO Sandrine

  CHRU Strasbourg

  PRINCIPAL INVESTIGATOR

• GONDOUIN Anne

  Centre Hospitalier Universitaire de Besancon

  PRINCIPAL INVESTIGATOR

• COURT-FORTUNE Isabelle

  CHU ST-ETIENNE

  PRINCIPAL INVESTIGATOR

• BONNIAUD Philippe

  CHU DIJON

  PRINCIPAL INVESTIGATOR

• QUETANT Sébastien

  University Hospital, Grenoble

  PRINCIPAL INVESTIGATOR

• GOMEZ Emmanuel

  CHU NANCY

  PRINCIPAL INVESTIGATOR

• BLANC François-Xavier

  Nantes University Hospital

  PRINCIPAL INVESTIGATOR

• MARQUETTE Charles-Hugo

  CHU NICE

  PRINCIPAL INVESTIGATOR

• MARCHAND-ADAM Sylvain

  CHRU TOURS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2016
• First Posted: December 13, 2016
• Study Start: January 20, 2017
• Primary Completion: July 24, 2019
• Study Completion: February 17, 2020
• Last Updated: December 30, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5)