Rituximab for Systemic sclerosis-associated interstitial lung disease

Inclusion criteria

• {"criterion_text":"- 1)\tMale and female 18 years and older who meet the American College of Rheumatology/EUropean League Against Rheumatism collaborative initiative (ACR/EULAR) classification criteria 2013 for systemic scleroderma.\n- 2)\tWho are eligible for a treatment with MMF (up to 1500 mg twice daily if tolerated) for the management of SSc-ILD adapted from the French PNDS (revised may 2022) [9]: -\tSevere ILD at the baseline assessment i.\twith an extensive ILD on HRCT ≥20% according to Goh classification [10] ii.\tor with forced vital capacity of the predicted value (% FVC) ≤ 70%. -\tor ILD regardless of HRCT extension and at high risk of progression (age > 60 years, male gender, early cutaneous diffuse SSc (≤ 5 years), Afro-American or Afro-Caribbean ethnicity, anti-SCL70/Topoisomerase I autoantibody, or biological inflammation with CRP >= 5 mg/L). -\tor ILD regardless of HRCT extension and with progression criteria in the past 6-24 months before the initial assessment (based on INBUILD study): i.\trelative decline in the forced vital capacity of the predicted value (% FVC) >=10% ii.\tor relative decline in FVC of 5-10% associated with a relative decline in DLCO >= 15% iii.\tor relative decline in FVC of 5-10% associated with worsening of dyspnea or extension of ILD lesion on HRCT iv.\tor worsening of dyspnea with extension of HRCT opacities\n- 3)\tPerson affiliated to a French social security system or equivalent\n- 4)\tWritten informed consent obtained from participant 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 on the care and contraception agreement form for women of childbearing potential because of use of mycophenolate\n- 5)\tAbility for subject to comply with the requirements of the study."}

Exclusion criteria

• {"criterion_text":"- 6)\tKnown diagnosis of significant respiratory disorders (asthma, tuberculosis, aspergillosis, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, smoking-related ILD), severe cardiomyopathy or a known severe heart failure as considered by the investigator\n- 15)\tTreatment with monoclonal antibodies (such as, but not limited to, etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab, tocilizumab) within 6 months prior to inclusion\n- 16)\tPatients on a lung transplant list\n- 17)\tPersons covered by articles L1121-5 to L1121-8 of the CSP (corresponding to all protected persons: pregnant women, parturients, nursing mothers, persons deprived of their liberty by judicial or administrative decision, minors, and persons subject to a legal protection measure: guardianship or trusteeship). Also, women of child-bearing potential (including female partners of sexually active men treated with mycophenolate) not using two reliable contraceptive methods and men not using a contraceptive method (condom), or women and men having a pregnancy project during the year following randomization\n- 18)\tPatients at high risk of infectious complications: Human Immunodeficiency Virus (HIV) positive or other known immunodeficiency syndromes, hepatitis B and C (HBV, HCV), COVID (within 3 month) or other known viral infection, infection requiring anti-infective treatment within 4 weeks of inclusion\n- 19)\tPatients with incomplete anti-SARS-CoV-2 vaccine regimen (according to current recommendations) and in this case, patient who has not receive treatment with anti SARS CoV2 therapeutic antibodies (ex : tixagévimab/cilgavimab).\n- 20)\tConcomitant participation in other interventional research with an investigational drug or medical device.\n- 7)\tKnown diagnosis of group 1 precapillary pulmonary hypertension (mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance > 2 UWood and FVC ≥ 70% theoretical) or group 3 severe precapillary pulmonary hypertension (mPAP > 20 mmHg and PAWP ≤ 15 mmHg and pulmonary vascular resistance > 5 UWood, whatever the FVC)\n- 8)\tConcomitant medical or surgical disease, clinically significant as considered by the investigator, serious or unstable, acute or chronically progressive, or any condition that could affect the safety of the patient, in the opinion of the investigator\n- 9)\tPatient who cannot walk more than 100 meters\n- 10)\tKnown MMF intolerance\n- 11)\tInitiation of a new therapy for SSc-ILD or with interruption / modification of therapy dosage within 4 weeks prior to baseline assessment\n- 12)\tPatient having already received a rituximab or MMF-based treatment line for SSc-ILD\n- 13)\tKnown hypersensitivity to rituximab, to murine proteins, other excipients or sulphonamide antibiotics.\n- 14)\tConcomitant immunosuppressive treatments: >15 mg/day corticosteroids, azathioprine, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, JAK inhibitors within 4 weeks prior to inclusion"}

Primary endpoints

• {"endpoint_text":"- The primary outcome is the change in Forced Vital Capacity (FVC) (in % predicted) from baseline to week 24 with measures at baseline, week 12 and week 24.","definition_or_measurement_approach":"Change in FVC expressed as % predicted from baseline to week 24; measurements recorded at baseline, week 12 and week 24."}

Secondary endpoints

• {"endpoint_text":"- 1)\tChange in % of predicted FVC (% FVC) from baseline to week 48","definition_or_measurement_approach":"Change in % predicted FVC from baseline to week 48."}
• {"endpoint_text":"- 2)\tChange in FVC (mL) from baseline to weeks 24 and 48","definition_or_measurement_approach":"Absolute change in FVC measured in mL at weeks 24 and 48 compared to baseline."}
• {"endpoint_text":"- 3)\tChange from baseline to weeks 24 and 48 in modified Rodnan skin score (mRSS)","definition_or_measurement_approach":"Change in mRSS score from baseline to weeks 24 and 48."}
• {"endpoint_text":"- 4)\tProgression free survival (PFS) to weeks 24 and 48, defined as the time to (first event considered): a)\ta first acute exacerbation, or b)\ta relative decline in the FVC of ≥ 10% of the predicted value, or c)\tinclusion on a lung transplant list, or d)\tinclusion for a therapeutic intensification by autologous haematological stem cell transplantation (AHSCT), or e)\tdeath.","definition_or_measurement_approach":"Time-to-event analysis up to weeks 24 and 48; first occurrence of listed events (acute exacerbation, ≥10% relative FVC decline, listing for lung transplant, referral for AHSCT, or death)."}
• {"endpoint_text":"- 5)\tOverall survival (OS)","definition_or_measurement_approach":"Time from randomization to death from any cause."}
• {"endpoint_text":"- 6)\tChanges from baseline to weeks 24 and 48 in the EULAR ScleroID questionnaire, King’s Brief Interstitial Lung Disease (K-BILD) questionnaire and LF-P symptom and impact questionnaire","definition_or_measurement_approach":"Patient-reported outcome changes measured by the listed questionnaires at weeks 24 and 48."}
• {"endpoint_text":"- 7)\tCumulative doses of corticosteroids at week 24 and 48","definition_or_measurement_approach":"Total corticosteroid dose accumulated up to weeks 24 and 48."}
• {"endpoint_text":"- 8)\tChanges from baseline to weeks 24 and 48 in % of predicted diffusing capacity for carbon monoxide (DLCO)","definition_or_measurement_approach":"Change in DLCO % predicted from baseline to weeks 24 and 48."}
• {"endpoint_text":"- 9)\tChanges from baseline to weeks 24 and 48 in the 6-minute walk test","definition_or_measurement_approach":"Change in distance covered in 6-minute walk test at weeks 24 and 48 versus baseline."}
• {"endpoint_text":"- 10)\tChange from baseline to week 24 in accelerometer-assessed physical activity","definition_or_measurement_approach":"Change in objectively measured physical activity (accelerometer) from baseline to week 24."}
• {"endpoint_text":"- 11)\tChanges from baseline to week 48 in high-resolution computed tomography (HRCT) of chest images","definition_or_measurement_approach":"Radiographic change in HRCT chest imaging between baseline and week 48 (extent/score as per protocol)."}
• {"endpoint_text":"- 12)\tChanges from baseline to week 48 of biological markers related to B-cell depletion: CD19 B-cells and gamma globulins","definition_or_measurement_approach":"Laboratory measurement of CD19 B-cell counts and gamma globulin levels at baseline and week 48 to assess B-cell depletion."}
• {"endpoint_text":"- 13)\t All adverse events, especially serious infectious adverse events, occurring during the 48 weeks treatment period","definition_or_measurement_approach":"Collection and reporting of all adverse events (with special attention to serious infectious events) throughout the 48-week treatment period."}
• {"endpoint_text":"- 14)\t Pharmacokinetic parameters of rituximab: volume of distribution, rituximab clearance and half-life","definition_or_measurement_approach":"Pharmacokinetic sampling to derive Vd, clearance and half-life parameters for rituximab."}

France

Earliest CTIS Part Ii Submission Date

25-07-2024

Latest Decision Or Authorization Date

01-10-2024

Processing Time Days

68

Number Of Sites

26

Number Of Participants

102

Primary sponsor

Full Name

Centre Hospitalier Regional Universitaire De Tours

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France