Interstitial Lung Disease With Systemic Sclerosis
Conditions
Brief summary
The goal of this clinical trial is to evaluate the efficacy on lung function after 24 weeks of rituximab + MMF combination comparatively to placebo + MMF combination in patients with SSc-ILD severe at the initial assessment or at high risk of progression.
Interventions
DRUGRituximab
one course of IV rituximab consisting of an infusion of 1000 mg rituximab (diluted in 500 mL of saline 0.9 % sodium chloride) will be given at day 1, day 15 and an infusion of 500 mg rituximab (in 500 mL of saline 0.9 % sodium chloride) at week 24;
DRUGPlacebo
one course of intravenous placebo of rituximab consisting of an infusion of 500 mL of saline (0.9% sodium chloride) infusion will be given at day 1, day 15 and week 24;
Sponsors
University Hospital, Tours
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Male 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. 2. Who 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) \[9\]: * Severe ILD at the baseline assessment i. with an extensive ILD on HRCT ≥20% according to Goh classification \[10\] ii. or with forced vital capacity of the predicted value (% FVC) ≤ 70%. * or 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). * or ILD regardless of HRCT extension and with progression criteria in the past 6-24 months before the initial assessment (based on INBUILD study): i. relative decline in the forced vital capacity of the predicted value (% FVC) \>=10% ii. or relative decline in FVC of 5-10% associated with a relative decline in DLCO \>= 15% iii. or relative decline in FVC of 5-10% associated with worsening of dyspnea or extension of ILD lesion on HRCT iv. or worsening of dyspnea with extension of HRCT opacities 3. Person affiliated to a French social security system or equivalent 4. Written 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 5. Ability for subject to comply with the requirements of the study.
Exclusion criteria
6. Known 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 7. Known 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) 8. Concomitant 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 9. Patient who cannot walk more than 100 meters 10. Known MMF intolerance 11. Initiation of a new therapy for SSc-ILD or with interruption / modification of therapy dosage within 4 weeks prior to baseline assessment 12. Patient having already received a rituximab or MMF-based treatment line for SSc-ILD 13. Known hypersensitivity to rituximab, to murine proteins, other excipients or sulphonamide antibiotics. 14. Concomitant immunosuppressive treatments: \>15 mg/day corticosteroids, azathioprine, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, JAK inhibitors within 4 weeks prior to inclusion 15. Treatment with monoclonal antibodies (such as, but not limited to, etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab, tocilizumab) within 6 months prior to inclusion 16. Patients on a lung transplant list 17. Persons 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 18. Patients 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 19. Patients 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). 20. Concomitant participation in other interventional research with an investigational drug or medical device.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced vital Capacity in % | At 24 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity in % | From baseline to weeks 48 | Change in % of predicted FVC (% FVC) |
| Forced Vital Capacity in mL | From baseline to weeks 24 and 48 | Change in FVC (mL) |
| Rodnan skin score | From baseline to weeks 24 and 48 | Change in modified Rodnan skin score (mRSS). This score assesses the extent of thickening at 17 points on the body, simply by palpating the skin. Thickening is from 0 to 3. 0 equals to normal skin thickness and 3 to severe thickening. |
| Progression free survival | At 24 and 48 weeks | First event considered |
| Overall survival | At 48 weeks | — |
| Scleroderma Health Assessment questionnaire | From baseline to weeks 24 and 48 | 23 questions divided into four groups related to symptoms of vascular, respiratory, gastrointestinal and musculoskeletal dysfunction |
| King's Brief Interstitial Lung Disease questionnaire | From baseline to weeks 24 and 48 | 15 questions about the impact of the disease on life. All answers are from 1 to 7. There is no maximum and minimum. |
| Living with pulmonary fibrosis symptom questionnaire | From baseline to weeks 24 and 48 | 23 questions to evaluate symptoms of pulmonary fibrosis |
| Living with pulmonary fibrosis impact questionnaire | From baseline to weeks 24 and 48 | 21 questions to determine how pulmonary fibrosis affects quality of life. |
| Diffusing capacity for carbon monoxide | From baseline to weeks 24 and 48 | Changes in % of predicted diffusing capacity for carbon monoxide |
| 6 minutes walk test | From baseline to weeks 24 and 48 | Changes in the 6 minute walk test |
| Physical activity | From baseline to week 24 | Change in accelerometer-assessed physical activity based on the number of steps per day |
| Chest image | From baseline to week 48 | Changes in HRCT chest images will be assessed by two thoracic radiologists expert in ILDs, who will score the extent of ILD and the severity of traction bronchiectasis. The ILD extent score will be estimated to the nearest 10% at three lung zones (delimited by the carina and the lowest inferior pulmonary vein for both lungs) and averaged between these 3 zones. Traction bronchiectasis scores will be scored between 0 and 3 (0=absence; 1=mild dilatation without tortuosity; 2=moderate dilatation, \< 6mm diameter, with tortuosity; 3=severe dilatation≥ 6mm) for the same three lung zones and averaged for the whole lungs. |
| Biological markers | From baseline to week 48 | Changes of biological markers related to B-cell depletion. Change in the number of CD19 lymphocytes in absolute value/liter |
| Advers events | From baseline to week 48 | Analyze of all adverse events, especially serious infectious adverse events, occurring during treatment period |
| Pharmacokinetic | At Day 1, day 15, week 12, week 24 and week 48 | Pharmacokinetic parameters of rituximab : volume of distribution in liter |
| Cumulative doses of corticosteroids | At week 24 and week 48 | — |
Countries
France
Outcome results
None listed