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

Lung Disease, Interstitial Clinical Trial

— EvER-ILD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02990286
• Other study ID #: PHRN15-SMA/EvER-ILD
• Status: Completed
• Phase: Phase 3
• Start date: January 20, 2017
• Est. completion date: February 17, 2020

Study information

• Verified date: November 2020
• Source: University Hospital, Tours
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: February 17, 2020
• Est. primary completion date: July 24, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lung Disease, Interstitial
• Lung Diseases
• Lung Diseases, Interstitial

Intervention

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

Locations

Country	Name	City	State
France	Chu Besancon	Besancon
France	Chu Dijon	Dijon
France	AP-HM Hôpital NORD	Marseille
France	Chu Rennes	Rennes
France	CHRU Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Cough evaluation	Changes in cough evaluation	Changes from baseline to 6 months in cough evaluation
Secondary	Cumulative doses of corticoids for the 2 groups	Cumulative doses of corticoids for the 2 groups	Cumulative doses of corticoids at 6 months
Secondary	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
Secondary	Changes in DLCO	Changes in DLCO	Changes from baseline to 6 months in DLCO
Secondary	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
Secondary	Changes in autoantibodies concentration	Changes in autoantibodies concentration	Changes from baseline to 6 months in autoantibodies concentration
Secondary	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
Secondary	Changes in gammaglobulins	Changes in gammaglobulins	Changes from baseline to 6 months in gammaglobulins
Secondary	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
Secondary	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
Secondary	Rituximab PK parameters : distribution volume	Rituximab PK parameters : distribution volume	Points at Day1, Day15, 3 and 6 months
Secondary	Rituximab clearance	Rituximab clearance	Points at Day1, Day15, 3 and 6 months
Secondary	Half-life of rituximab in blood	Half-life of rituximab in blood	Points at Day1, Day15, 3 and 6 months