Clinical trial NCT02990286: Evaluation of Efficacy and Safety of Rituximab With Mycophenolate Mofetil in Patients With Interstitial Lung Diseases
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lung Disease, Interstitial
Keywords: Non specific intertitial pneumonia
interstitial pneumonia with autoimmune feature
connective tissue disease
rituximab
Mycophenolate Mofetil
pulmonary fibrosis
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2016-12-13
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change in FVC in % of predicted
timeFrame: From baseline to 6 months
Secondary outcomes:
measure: Progression Free Survival (PFS).
timeFrame: PFS measured at 3, 6 and 12 months
measure: Changes in the quality of life score
timeFrame: 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
measure: Changes in the visual analogic scales of dyspnea
timeFrame: 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
measure: Cough evaluation
timeFrame: Changes from baseline to 6 months in cough evaluation
measure: Cumulative doses of corticoids for the 2 groups
timeFrame: Cumulative doses of corticoids at 6 months
measure: Changes in the FVC expressed as % of predicted
timeFrame: Changes from baseline to 3 and 6 months in the FVC expressed as % of predicted
measure: Changes in DLCO
timeFrame: Changes from baseline to 6 months in DLCO
measure: Changes in the 6-minutes-walk test
timeFrame: Changes from baseline to 6 months in the 6-minutes-walk test
measure: Changes in autoantibodies concentration
timeFrame: Changes from baseline to 6 months in autoantibodies concentration
measure: Changes in biological markers related to lymphocyte B depletion: CD19 lymphocytes
timeFrame: Changes from baseline to 6 months in lymphocytes B CD19
measure: Changes in gammaglobulins
timeFrame: Changes from baseline to 6 months in gammaglobulins
measure: Changes in HRCT of the chest images
timeFrame: Changes from baseline to 6 months in HRCT of the chest images
measure: Adverse events related to treatment
timeFrame: Adverse events during the 6 months of study period
measure: Rituximab PK parameters : distribution volume
timeFrame: Points at Day1, Day15, 3 and 6 months
measure: Rituximab clearance
timeFrame: Points at Day1, Day15, 3 and 6 months
measure: Half-life of rituximab in blood
timeFrame: Points at Day1, Day15, 3 and 6 months
Other outcomes:
Locations:
city: Besancon
country: France
facility: Chu Besancon
city: Dijon
country: France
facility: Chu Dijon
city: Marseille
country: France
facility: AP-HM Hôpital NORD
city: Rennes
country: France
facility: Chu Rennes
city: Tours
country: France
facility: CHRU Tours
Study officials:
affiliation: HC LYON
name: TRACLET Julie
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP - Hôpital Avicenne
name: NUNES Hilario
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP - Hôpital Bichat
name: CRESTANI Bruno
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP HEGP
name: ISRAEL BIET Dominique
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP - Hôpital Tenon
name: NACCACHE Jean-Marc
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU LILLE
name: WEMEAU Lidwine
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Rennes
name: JOUNEAU Stéphane
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Toulouse
name: PREVOT Grégoire
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HM Hôpital Nord
name: REYNAUD-GAUBERT Martine
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU Strasbourg
name: HIRSCHI SANTELMO Sandrine
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Universitaire de Besancon
name: GONDOUIN Anne
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU ST-ETIENNE
name: COURT-FORTUNE Isabelle
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU DIJON
name: BONNIAUD Philippe
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: QUETANT Sébastien
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU NANCY
name: GOMEZ Emmanuel
role: PRINCIPAL_INVESTIGATOR
affiliation: Nantes University Hospital
name: BLANC François-Xavier
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU NICE
name: MARQUETTE Charles-Hugo
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU TOURS
name: MARCHAND-ADAM Sylvain
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.