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

• ClinicalTrials.gov Identifier: NCT02990286
• Recruitment Status: Completed
• First Posted: December 13, 2016
• Last Update Posted: November 4, 2020
• Sponsor: University Hospital, Tours
• Information provided by (Responsible Party): University Hospital, Tours

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Lung Disease, Interstitial	Drug: Rituximab; Drug: Placebo of Rituximab; Drug: Mycophenolate Mofetil	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 20, 2017
• Actual Primary Completion Date: July 24, 2019
• Actual Study Completion Date: February 17, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in FVC in % of predicted [ Time Frame: From baseline to 6 months ]
   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

Secondary Outcome Measures :

1. Progression Free Survival (PFS). [ Time Frame: PFS measured at 3, 6 and 12 months ]
   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
2. Changes in the quality of life score [ Time Frame: 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 ]
   The quality of life score as measured by the SF-36 v1.3 questionnaire, version developed and validated in interstitial lung disease (ILD) patients.
3. Changes in the visual analogic scales of dyspnea [ Time Frame: 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 (EVA test)
4. Cough evaluation [ Time Frame: Changes from baseline to 6 months in cough evaluation ]
   Changes in cough evaluation
5. Cumulative doses of corticoids for the 2 groups [ Time Frame: Cumulative doses of corticoids at 6 months ]
   Cumulative doses of corticoids for the 2 groups
6. Changes in the FVC expressed as % of predicted [ Time Frame: Changes from baseline to 3 and 6 months in the FVC expressed as % of predicted ]
   Changes in the FVC expressed as % of predicted
7. Changes in DLCO [ Time Frame: Changes from baseline to 6 months in DLCO ]
   Changes in DLCO
8. Changes in the 6-minutes-walk test [ Time Frame: Changes from baseline to 6 months in the 6-minutes-walk test ]
   Changes in the 6-minutes-walk test
9. Changes in autoantibodies concentration [ Time Frame: Changes from baseline to 6 months in autoantibodies concentration ]
   Changes in autoantibodies concentration
10. Changes in biological markers related to lymphocyte B depletion: CD19 lymphocytes [ Time Frame: Changes from baseline to 6 months in lymphocytes B CD19 ]
    Changes in biological markers related to lymphocyte B depletion: CD19 lymphocytes
11. Changes in gammaglobulins [ Time Frame: Changes from baseline to 6 months in gammaglobulins ]
    Changes in gammaglobulins
12. Changes in HRCT of the chest images [ Time Frame: Changes from baseline to 6 months in HRCT of the chest images ]
    Changes in HRCT of the chest images
13. Adverse events related to treatment [ Time Frame: Adverse events during the 6 months of study period ]
    In particular infectious adverse events and biological blood disorders during the 6 months of study period will be collected
14. Rituximab PK parameters : distribution volume [ Time Frame: Points at Day1, Day15, 3 and 6 months ]
    Rituximab PK parameters : distribution volume
15. Rituximab clearance [ Time Frame: Points at Day1, Day15, 3 and 6 months ]
    Rituximab clearance
16. Half-life of rituximab in blood [ Time Frame: Points at Day1, Day15, 3 and 6 months ]
    Half-life of rituximab in blood

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

France

Chu Besancon

Besancon, France, 25030

Chu Dijon

Dijon, France, 21079

AP-HM Hôpital NORD

Marseille, France, 13015

Chu Rennes

Rennes, France, 35033

CHRU Tours

Tours, France, 37044

Sponsors and Collaborators

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 - Hôpital 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 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; CHU Nantes
• Principal Investigator: MARQUETTE Charles-Hugo; CHU NICE
• Principal Investigator: MARCHAND-ADAM Sylvain; CHRU TOURS

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University Hospital, Tours
• ClinicalTrials.gov Identifier: NCT02990286
• Other Study ID Numbers: PHRN15-SMA/EvER-ILD
• First Posted: December 13, 2016
• Last Update Posted: November 4, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Tours:

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

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Interstitial; Respiratory Tract Diseases; Mycophenolic Acid; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action