Rituximab vs Placebo for Maintenance in Systemic Sclerosis - Interstitial Lung Disease

Systemic sclerosis (SSc) is a rare autoimmune connective tissue-disease. Interstitial lung disease (ILD) is a common manifestation and a leading cause of death in SSc.

Rituximab (RTX) is commonly used in SSc-ILD induction treatment and recent trials have now fully demonstrated its safety and efficacy as an induction treatment. The DESIRES trial reported that RTX-induction was associated with a 24-week stabilization of FVC. As evaluated by the FVC at 24 weeks from baseline, 25 patients with SSc-ILD treated with RTX were significantly improved compared with 23 patients treated with placebo (0.09% vs -2.87%; [95%CI 0.08-5.84]; p < 0.05). Recently, the RECITAL trial showed the absence of difference between induction treatment with cyclophosphamide (CYC) and RTX in ILD including SSc-ILD. Indeed, both RTX and CYC resulted in an improvement in FVC (97 ± 234mL and 99 ± 329mL respectively) at 24 weeks, without significant statistical difference in 101 subjects. Furthermore, the EVER-ILD study, also very recently presented, reported a beneficial of RTX in addition to mycophenolate mofetil (MMF) over RTX in CTD-ILD. Altogether with previous European database studies which analyzed the very common usage of RTX as induction therapy in SSc, these studies have confirmed its efficient and safe role as an induction treatment in SSc-ILD.

Still, the impact of re-treatment with RTX in maintaining ILD-stabilization has never been studied and deserve to be studied.

The hypothesis that drives the MAINRITSyS is that RTX maintains ILD stabilization in SSc-ILD.

Inclusion criteria

• Adult patient (≥ 18 years old),
• Patient with a diagnosis of SSc, as defined by the ACR/EULAR 2013 criteria (cf. Table 2) (6)
• Patient with ILD identified on the basis of a HRCT, obtained within 12 months before screening, that showed fibrosis affecting at least 10% of the lungs,
• SSc-ILD induction with RTX, either twice 1000 mg two weeks apart, or 375 mg/m2 four times 4 weeks apart.

The interval between the last induction dose and the first maintenance dose should be 6 months +/- 15 days.

• Patient with stabilized SSc-ILD following RTX induction treatment as defined by the absence of worsening respiratory symptoms, an absolute decline of FVC of < 5% of the predicted value, an absence of absolute decline of DLCO (corrected for hemoglobin) of < 10% related to SSc-ILD, and absence of radiological evidence of disease progression on HRCT(97)
• All required vaccinations must have been carried out at least 4 weeks before D0. According to recommendations, prophylaxis against pneumocystis is recommended for scleroderma, but not mandatory.
• Woman of childbearing potential should have reliable contraception* for the 12 months' duration of the study's treatment and 12 months after last administration,
• Patient able to give written informed consent prior to participation in the study,
• Affiliation to a social security scheme (profit or being entitled). AME is not accepted.

Exclusion criteria

• Forced vital capacity < 40% of the predicted value
• Diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) < 30% of the predicted value.
• Contra-indication or anaphylaxis toward RTX
• Contra-indication to auxiliary medicinal products
• Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening
• Any biologic therapy (including other anti-CD20, anti-CD19, or anti-plasma cell) such as, but not limited to, belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to screening or during screening
• Inhibitors of Janus-associated kinase (JAK), Bruton's tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening
• Any live vaccine during the 28 days prior to screening or during screening
• High risk for clinically significant bleeding or any condition requiring plasmapheresis, IV immunoglobulin, or acute blood product transfusions during the 28 days prior the screening
• Active infection with SARS-CoV-2 or absence of COVID-19 vaccination within the last six months (this criteria will be updated at the time of submission to European Agency to be in adequation with national recommendation at the time of submission).
• Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude patient participation
• HIV infection : for participants with unknown HIV status (if the previous tests date more than 3 months), HIV testing will be performed locally at screening.
• Tuberculosis (TB) infection: Testing for latent TB will be performed locally at screening if required by local regulations or in accordance with local clinical practice. Latent TB after completion of appropriate treatment is not exclusionary
• Active infection of any kind, excluding fungal infection of the nail beds.
• History of serious recurrent or chronic infection
• History of progressive multifocal leukoencephalopathy (PML)
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years. Participants with non-melanomatous carcinomas of the skin that have been treated or excised and have resolved are eligible.
• Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening
• Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening
• History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the RTX infusion
• Any of the following laboratory parameters:

• AST or ALT above 2.5 upper limit normal range
• Neutrophils <1.5x103/mL
• Positive hepatitis B surface antigen (HBsAg)
• Positive hepatitis C serology Participants with positive hepatitis C antibody test result with no detectable hepatitis C virus (HCV) RNA for at least 6 months after completion of antiviral therapy are eligible but will require monthly HCV RNA monitoring until 12 months after the last dose of RTX or placebo.
• Pregnancy or breastfeeding
• Participation in another interventional study or being in the exclusion period at the end of a previous study.
• Participants under court supervision, guardianship, or conservatorship.