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

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ClinicalTrials.gov Identifier: NCT02990286
Recruitment Status : Recruiting
First Posted : December 13, 2016
Last Update Posted : May 8, 2017
Sponsor:
Information provided by (Responsible Party):
University Hospital, Tours

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 Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : January 2021


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.





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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02990286


Contacts
Contact: MARCHAND-ADAM Sylvain 2 47 47 98 34 ext +33 sylvain.marchand-adam@univ-tours.fr

Locations
France
Chu Besancon Recruiting
Besancon, France, 25030
Contact: GONDOUIN Anne         
Chu Dijon Recruiting
Dijon, France, 21079
Contact: BONNIAUD Philippe         
AP-HM Hôpital NORD Recruiting
Marseille, France, 13015
Contact: REYNAUD-GAUBERT Martine         
Chu Rennes Recruiting
Rennes, France, 35033
Contact: JOUNEAU Stéphane         
CHRU Tours Recruiting
Tours, France, 37044
Contact: MARCHAND-ADAM Sylvain         
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

Responsible Party: University Hospital, Tours
ClinicalTrials.gov Identifier: NCT02990286     History of Changes
Other Study ID Numbers: PHRN15-SMA/EvER-ILD
First Posted: December 13, 2016    Key Record Dates
Last Update Posted: May 8, 2017
Last Verified: May 2017
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
Rituximab
Mycophenolic Acid
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