Evaluation of Efficacy and Safety of Rituximab With Mycophenolate Mofetil in Patients With Interstitial Lung Diseases (EvER-ILD)

Evaluation of Efficacy and Safety of Rituximab in Association With Mycophenolate Mofetil Versus Mycophenolate Mofetil Alone in Patients With Interstitial Lung Diseases (ILD) Non-responders to a First-line Immunosuppressive Treatment

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.

Study Overview

• Status: Completed
• Conditions: Lung Disease, Interstitial
• Intervention / Treatment: Drug: Rituximab; Drug: Mycophenolate Mofetil; Drug: Placebo of Rituximab

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Besancon, France, 25030
    • CHU Besançon
  • Dijon, France, 21079
    • CHU Dijon
  • Marseille, France, 13015
    • AP-HM Hôpital Nord
  • Rennes, France, 35033
    • Chu Rennes
  • Tours, France, 37044
    • CHRU Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years

2. A diagnosis of ILD:

   • ILD associated with differentiated CTD or IPAF (based on internationally accepted criteria)
   • OR idiopathic ILD

3. 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
4. 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.
5. Subjects covered by or having the rights to French social security (including CMU),
6. 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.
7. Ability for subject to comply with the requirements of the study

Exclusion Criteria:

1. Known diagnosis of significant respiratory disorders (asthma, tuberculosis, sarcoidosis, aspergillosis, or cystic fibrosis) other than CTD-NSIP, IPAF-NSIP and iNSIP
2. 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.
3. HRCT pattern of typical usual interstitial pneumonia (UIP)
4. For patients with idiopathic ILD, HRCT pattern of possible UIP (no evocative of NSIP)
5. Histological pattern other than pattern of NSIP
6. A first line treatment with MMF or rituximab
7. Known hypersensitivity to MMF or rituximab or sulfonamide antibiotics

8. Treatment with immunosuppressive treatments other than corticosteroids:

   • azathioprine, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, leflunomide within 2 weeks (5 half-lives <= 2 weeks) prior to inclusion
   • intravenous immunoglobulins, hydroxychloroquine or other monoclonal antibody therapies (such as but not limited to etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab) within 6 months (5 half-lives <= 6 months) prior to inclusion
9. Patients registered on a pulmonary transplantation list
10. Patients with known hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) hereditary deficiency (such as Lesch-Nyhan and Kelley-Seegmiller syndrome)
11. 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.
12. 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
13. Current history of substance and/or alcohol abuse
14. Deprivation of liberty, under judicial protection
15. Participation in another biomedical research with experimental 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
Experimental: Rituximab with Mycophenolate Mofetil	Drug: Rituximab; 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); Drug: Mycophenolate Mofetil; Mycophenolate Mofetil 500mg film-coated tablets 1 gram twice daily on oral route of MMF (= 2 grams daily) for 6 months.
Placebo Comparator: Placebo of rituximab with Mycophenolate Mofetil	Drug: Mycophenolate Mofetil; Mycophenolate Mofetil 500mg film-coated tablets 1 gram twice daily on oral route of MMF (= 2 grams daily) for 6 months.; Drug: Placebo of Rituximab; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS).	PFS is defined as the time 1) to the first acute exacerbation, or 2) to an absolute decline of 10 % points in the percentage of the predicted FVC, or 3) to the necessity to withdraw the MMF with/without a new immunosuppressive treatment (except corticoids), or 4) to death or 5) registration to a lung transplantation list. An acute exacerbation is defined by (1) progressive dyspnea over 1 month or less; (2) new pulmonary infiltrates on chest radiography or computed tomography, and (3) the absence of an overt underlying cause of rapid deterioration	PFS measured at 3, 6 and 12 months
Changes in the quality of life score	The quality of life score as measured by the SF-36 v1.3 questionnaire, version developed and validated in interstitial lung disease (ILD) patients.	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 in the visual analogic scales of dyspnea (EVA test)	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 in cough evaluation	Changes from baseline to 6 months in cough evaluation
Cumulative doses of corticoids for the 2 groups	Cumulative doses of corticoids for the 2 groups	Cumulative doses of corticoids at 6 months
Changes in the FVC expressed as % of predicted	Changes in the FVC expressed as % of predicted	Changes from baseline to 3 and 6 months in the FVC expressed as % of predicted
Changes in DLCO	Changes in DLCO	Changes from baseline to 6 months in DLCO
Changes in the 6-minutes-walk test	Changes in the 6-minutes-walk test	Changes from baseline to 6 months in the 6-minutes-walk test
Changes in autoantibodies concentration	Changes in autoantibodies concentration	Changes from baseline to 6 months in autoantibodies concentration
Changes in biological markers related to lymphocyte B depletion: CD19 lymphocytes	Changes in biological markers related to lymphocyte B depletion: CD19 lymphocytes	Changes from baseline to 6 months in lymphocytes B CD19
Changes in gammaglobulins	Changes in gammaglobulins	Changes from baseline to 6 months in gammaglobulins
Changes in HRCT of the chest images	Changes in HRCT of the chest images	Changes from baseline to 6 months in HRCT of the chest images
Adverse events related to treatment	In particular infectious adverse events and biological blood disorders during the 6 months of study period will be collected	Adverse events during the 6 months of study period
Rituximab PK parameters : distribution volume	Rituximab PK parameters : distribution volume	Points at Day1, Day15, 3 and 6 months
Rituximab clearance	Rituximab clearance	Points at Day1, Day15, 3 and 6 months
Half-life of rituximab in blood	Half-life of rituximab in blood	Points at Day1, Day15, 3 and 6 months

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: 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 - Hopital Tenon; Principal Investigator: WEMEAU Lidwine, CHRU Lille; Principal Investigator: JOUNEAU Stéphane, Chu Rennes; Principal Investigator: PREVOT Grégoire, CHU 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 Besançon; 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, CHU Nantes; Principal Investigator: MARQUETTE Charles-Hugo, CHU Nice; Principal Investigator: MARCHAND-ADAM Sylvain, CHRU Tours

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2017
• Primary Completion (Actual): July 24, 2019
• Study Completion (Actual): February 17, 2020

Study Registration Dates

• First Submitted: November 25, 2016
• First Submitted That Met QC Criteria: December 8, 2016
• First Posted (Estimate): December 13, 2016

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: rituximab; Mycophenolate Mofetil; connective tissue disease; pulmonary fibrosis; Non specific intertitial pneumonia; interstitial pneumonia with autoimmune feature
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Rituximab; Mycophenolic Acid
• Other Study ID Numbers: PHRN15-SMA/EvER-ILD

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