OBINUSS - A trial to evaluate a new drug in systemic sclerosis: obinutuzumab.

Prior treatment

• 10-Active infection of any kind, excluding fungal infection of the nail beds. Any major episode of infection that also fulfills any of the following criteria: * Requires hospitalization during the 8 weeks prior to screening or during screening * Requires treatment with IV antibiotics (or anti-infectives) during the 8 weeks prior to screening or during screening * Requires treatment with oral antibiotics (or anti-infectives) during the 2 weeks prior to screening or during screening * Antibiotics or anti-infectives given in the absence of a major episode of infection are not exclusionary.
• 14-Major surgery requiring hospitalization during the 4 weeks prior to or during screening
• 15-Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening
• 2-Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening
• 21- Patients treated with CAR-T cell immunotherapy.
• 3-Any biologic therapy (other than 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
• 4-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
• 5-Any live vaccine during the 28 days prior to screening or during screening
• 6-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

Other illness

• 11-History of serious recurrent or chronic infection
• 12-History of progressive multifocal leukoencephalopathy (PML)
• 13-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).
• 16-Intolerance or contraindication to study therapies, including any of the following: *History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion
• 7-Active infection with SARS-CoV-2 or patients not fully vaccinated following national recommendations against SARS-CoV-2
• 8-Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation
• 9-HIV infection: for participants with unknown HIV status, HIV testing will be performed locally at screening if required by local regulations.

Lab values

• 1-Any B-cell depleting (e.g., anti-CD20, anti-CD19) or anti-plasma cell therapy such as, but not limited to, obinutuzumab, rituximab, ocrelizumab, ofatumumab, or bortezomib less than 9 months prior to screening or during screening. If anti-CD20 or anti-CD19 therapy has been received between 9 and 12 months prior to screening, the peripheral CD19+ B-cell count must be over 25 cells/µL
• 17-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) Participants who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring until 12 months after the last dose of obinutuzumab or placebo. * 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 obinutuzumab or placebo. * Hemoglobin below 7 g/dL * Platelet count below 50,000/L

Other

• 18-Pregnant or breastfeeding woman, or woman who refuses to use an effective contraception during the study course;
• 19-Protected adults (including individual under legal guardianship by court order or curatorship) or adults deprived of liberty;
• 20-Patient participating in another investigational therapeutic study in the 3 months preceding inclusion;

• 1-Adult patient (>/= 18 years old),
• 10- Anti-fibrotic drugs such as nintedanib is permitted
• 2-Patient with a diagnosis of SSc, as defined by the American College of Rheumatology / EULAR 2013 criteria,
• 3-Patient with a diffuse SSc, as defined according to Leroy et al.
• 4-Patient with a SSc disease duration of less than 8 years (defined as time from first non-Raynaud phenomenon manifestation) or with an active SSc disease, as defined by EUSTAR disease activity score,
• 5- Patient with a modified Rodnan skin score (mRSS) > /= 10 and < /= 35 units at screening,
• 6-Negative pregnancy test for woman of childbearing potential, woman of childbearing potential should have reliable contraception during the treatment period and up to 18 months after stopping it
• 7-Patient able to give written informed consent prior to participation in the study,
• 8-Affiliation to a social security scheme (profit or being entitled).
• 9- If patients receive mycophenolate or methotrexate for SSc, these need to be on stable dose as follows: Mycophenolate mofetil/sodium: stable dose for at least 2 months prior to randomisation Methotrexate: stable dose and route of administration for at least 2 months prior to randomisation