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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lung Disease, Interstitial

Intervention / Treatment
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* Drug: Rituximab
* Drug: Placebo of Rituximab
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab with Mycophenolate Mofetil<br> | Drug: Rituximab<br>* 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)<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil 500mg film-coated tablets 1 gram twice daily on oral route of MMF (= 2 grams daily) for 6 months.<br>|
| Placebo Comparator: Placebo of rituximab with Mycophenolate Mofetil<br> | Drug: Placebo of Rituximab<br>* 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)<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil 500mg film-coated tablets 1 gram twice daily on oral route of MMF (= 2 grams daily) for 6 months.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non specific intertitial pneumonia, interstitial pneumonia with autoimmune feature, connective tissue disease, rituximab, Mycophenolate Mofetil, pulmonary fibrosis