Obinutuzumab in Systemic Sclerosis

Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue-disease characterized by fibrosis, inflammation, and vasculopathy. SSc is responsible for skin fibrosis that can either be limited or diffuse. The latter phenotype of the disease is commonly associated with visceral involvement and therefore similar to graft versus host disease (GvHD) reaction. It can be life threatening in case of pulmonary or cardiovascular involvement. Nonetheless SSc remains a severe disease responsible for important disability and a poor quality of life.

B cell depletion and anti CD20 antibody (rituximab) have proven safety and efficacy in treating diffuse SSc. Obinutuzumab is a new generation anti-CD20 antibody for which efficacy and safety should be evaluated in SSc.

The OBINUSS trial was thus designed to evaluate obinutuzumab safety and efficacy in SSc.

Inclusion criteria

• Adult patient (>/= 18 years old),
• Patient with a diagnosis of SSc, as defined by the American College of Rheumatology / EULAR 2013 criteria,
• Patient with a diffuse SSc, as defined according to Leroy et al.
• 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,
• Patient with a modified Rodnan skin score (mRSS) > /= 10 and < /= 35 units at screening,
• 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 Women are considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
• Patient able to give written informed consent prior to participation in the study,
• Affiliation to a social security scheme (profit or being entitled).
• 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

• Anti-fibrotic drugs such as nintedanib is permitted

Exclusion criteria

• 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
• Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening
• 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
• 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 patients not fully vaccinated following national recommendations against SARS-CoV-2
• Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude patient participation
• HIV infection: for participants with unknown HIV status, HIV testing will be performed locally at screening if required by local regulations.
• 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.
• 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 or during screening
• Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening
• 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

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