Obinutuzumab for Cryoglobulinemia vasculitis | Mixed cryoglobulinemia

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years"}
• {"criterion_text":"- Written informed consent"}
• {"criterion_text":"- Active mixed cryoglobulinemia vasculitis defined by: a clinically active vasculitis signs with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement, and history of positive cryoglobulinemia and/or positive Rheumatoid factor associated with low C4 complement level, and/or a monoclonal component (IgM Kappa) and/or a histological proof of vasculitis in the affected organs"}
• {"criterion_text":"- Refractory or intolerant to Rituximab. Refractory patients are defined as any of the following after a standard rituximab regimen (375 mg/m² IV weekly for 4 consecutive weeks): -\tNo measurable improvement within 4–6 weeks of initiation, -\tOR <50% improvement in the number or severity of affected organ systems at 12 weeks, or -\tOR Persistent baseline manifestations without remission or significant improvement for >12 weeks. Improvement: A measurable positive change in the clinical signs, symptoms, and/or functional status of the affected organ(s), compared to baseline, as assessed using the organ-specific criteria below, without fulfilling full remission requirements. Remission: Complete disappearance of all baseline symptoms and objective abnormalities in the affected organ(s), as defined below: -\tThe skin and articular remissions are evaluated clinically (disappearance of purpura and ulcers, disappearance of arthritis, disappearance of the skin necrosis). -\tRenal remission is evaluated biologically (proteinuria <0.5g/24h or proteinuria/creatininuria <50 mg/mmol), and improvement of GFR >20% if GFR <60 mL/min/1.73 m2 at diagnosis or glomerular filtration rate ≥60ml/min/1.73m² if GFR ≥ 60 mL/min1.73 m2 at diagnosis -\tPeripheral Neurological remission is evaluated clinically (any improvement of pains and paresthesia by visual analogue scales, any stabilization or improvement of muscular testing in case of motor impairment at baseline) and electrophysiologically (stabilization or improvement of electromyogram abnormalities compared to baseline). -\tCentral Neurological remission is evaluated clinically (no new neurological symptoms and stabilization or improvement of the initial presentation) and radiologically (Cerebral MRI showing no new lesions and no contrast enhancement of the initial lesions, or regression of the initial lesion) -\tDigestive remission is evaluated clinically (resolution of abdominal pain and other gastrointestinal symptoms), and by endoscopy (resolution of potential gastrointestinal lesions seen at baseline) and/or by CT scan (resolution of any abnormalities found on baseline imaging). Complete remission of all baseline abnormalities is required to define digestive remission. -\tCardiac remission is evaluated clinically (resolution of chest pains and other cardiac events), and biologically (normalization of myocardial enzymes) and radiologically (no late gadolinium enhancement on cardiac MRI). Complete remission of all baseline abnormalities is required to define the cardiac remission. Pulmonary remission: complete regression of the initial symptoms with no new radiological lesions and regression of all the initial lesions. Intolerant: Patients who experienced treatment-limiting adverse events or toxicity that required discontinuation of rituximab, despite dose modification or supportive care."}
• {"criterion_text":"- HIV negative serology within 3 months prior inclusion"}
• {"criterion_text":"- Negative HBs Ag test. within 3 months prior inclusion"}
• {"criterion_text":"- HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion"}
• {"criterion_text":"- \tAffiliated to National French social security system (registered or being a beneficiary of such a scheme). Patients with AME are eligible."}

Exclusion criteria

• {"criterion_text":"- Vasculitis unrelated to cryoglobulinemia"}
• {"criterion_text":"- Have a history of an anaphylactic reaction to parenteral administration of Obitunuzumab"}
• {"criterion_text":"- Pregnant or breastfeeding women, or desire to become pregnant within 30 months"}
• {"criterion_text":"- All women of childbearing potential (WOCBP) are required to have a negative pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using an effective method of birth control from the date of consent until 18 months after the last obinutuzumab infusion: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (Oral, Intravaginal, Transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (Oral, Injectable, Implantable); Intrauterine device (IUD); Intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomised partner"}
• {"criterion_text":"- Neutrophils < 1000/mm3 or Platelets < 50000/mm3"}
• {"criterion_text":"- Unstable or high-risk cardiac conditions, e.g., recent (<6 months) myocardial infarction or unstable angina, decompensated (NYHA III–IV) heart failure, clinically significant uncontrolled arrhythmias, or any cardiac condition that, in the investigator’s judgment, poses an unacceptable risk with obinutuzumab infusion"}
• {"criterion_text":"- Live vaccines within 30 days prior inclusion"}
• {"criterion_text":"- Patients under guardianship or curatorship and protected adults or unable to consent"}
• {"criterion_text":"- Progressive multifocal leukoencephalopathy"}
• {"criterion_text":"- Participation to another interventional study"}
• {"criterion_text":"- Non-active cryoglobulinemia vasculitis"}
• {"criterion_text":"- Treatment with cyclophosphamide or Belimumab within 3 months prior to inclusion"}
• {"criterion_text":"- Malignant neoplasm within the last 5 years other than carcinoma in situ of the cervix or excised basal cell, squamous cell carcinoma of the skin and low-grade hemopathy with no indication for a specific treatment. Carcinoma in situ of the cervix and squamous cell carcinoma of the skin should have been adequately treated before inclusion in the study."}
• {"criterion_text":"- Active tuberculosis, pneumocystis, cytomegalovirus or any active infection not adequately managed or considered a risk by the investigator"}

Primary endpoints

• {"endpoint_text":"- Complete clinical response of CV at 6 months. Complete remission of CV is defined as remission of all affected organs involved at baseline and with corticosteroid withdrawal in the absence of severe clinical relapse.","definition_or_measurement_approach":"Complete remission is defined as remission of all affected organs involved at baseline and with corticosteroid withdrawal in the absence of severe clinical relapse; assessed at 6 months."}

Secondary endpoints

• {"endpoint_text":"- Frequency and severity of adverse clinical events at W12, W24 and W48","definition_or_measurement_approach":"Assessed at weeks 12, 24 and 48; frequency and severity graded per clinical event reporting (timepoints specified)."}
• {"endpoint_text":"- Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response at W12, W24 and W48 (See section 8.1)","definition_or_measurement_approach":"Categorical response rates evaluated at weeks 12, 24 and 48; complete response includes corticosteroid withdrawal to prednisone 0 mg/day."}
• {"endpoint_text":"- Rate of patients with complete renal remission at W12, W24 and W48 defined as proteinuria <0.5g/24h or proteinuria/creatininuria <50 mg/mmol, and improvement of GFR >20% if GFR <60 mL/min/1.73 m² at diagnosis or GFR > 60 mL/min/1.73 m² if GFR ≥60ml/min/1.73m² at diagnosis.","definition_or_measurement_approach":"Renal remission explicitly defined by proteinuria and creatininuria thresholds and GFR improvement criteria; assessed at weeks 12, 24 and 48."}
• {"endpoint_text":"- Rate of patients without cryoglobulinemia at W12, W24 and W48","definition_or_measurement_approach":"Assessed by laboratory cryoglobulin measurement at weeks 12, 24 and 48."}
• {"endpoint_text":"- Rate of patients without rheumatoid factor activity at W12, W24 and W48","definition_or_measurement_approach":"Assessed by rheumatoid factor activity laboratory tests at weeks 12, 24 and 48."}
• {"endpoint_text":"- Rate of patients with normal C4 complement level at W12, W24 and W48","definition_or_measurement_approach":"Assessed by serum C4 complement level at weeks 12, 24 and 48."}
• {"endpoint_text":"- Rate of patients with early treatment failure defined as the absence of clinical response at W4","definition_or_measurement_approach":"Early treatment failure = absence of clinical response at week 4."}
• {"endpoint_text":"- Cumulative incidence of clinical relapse (severe or non-severe) defined by reappearance of a manifestation attributable to cryoglobulinemia vasculitis from baseline to the end of follow-up","definition_or_measurement_approach":"Cumulative incidence from baseline to end of follow-up; relapse defined by reappearance of attributable manifestations."}
• {"endpoint_text":"- Cumulative incidence of severe clinical relapse from baseline to the end of follow-up","definition_or_measurement_approach":"Cumulative incidence of severe relapses from baseline to end of follow-up."}
• {"endpoint_text":"- Cumulative incidence of mild or moderate clinical relapse from baseline to the end of follow up","definition_or_measurement_approach":"Cumulative incidence of mild/moderate relapses from baseline to end of follow-up."}
• {"endpoint_text":"- Cumulative dose of prednisone at W24 and at W48.","definition_or_measurement_approach":"Total cumulative prednisone dose measured at weeks 24 and 48."}
• {"endpoint_text":"- BVAS activity score variation from baseline to W12, W24 and W48","definition_or_measurement_approach":"Change in Birmingham Vasculitis Activity Score (BVAS) from baseline to weeks 12, 24 and 48."}
• {"endpoint_text":"- Variation in physical and mental summary components of score SF-36 from baseline to W24 and to W48","definition_or_measurement_approach":"Change in SF-36 physical and mental summary scores from baseline to weeks 24 and 48."}
• {"endpoint_text":"- Cumulative incidence of infections (severe or non-severe) from baseline to W48","definition_or_measurement_approach":"Cumulative incidence of infections recorded from baseline to week 48; severity graded per protocol."}
• {"endpoint_text":"- Cumulative incidence of severe infections from baseline to W48","definition_or_measurement_approach":"Cumulative incidence of severe infections from baseline to week 48."}
• {"endpoint_text":"- Cumulative incidence of non-severe infections from baseline to W48","definition_or_measurement_approach":"Cumulative incidence of non-severe infections from baseline to week 48."}
• {"endpoint_text":"- Cumulative incidence of non-infectious complications (cancer, lymphoma, cardiovascular event: stroke, myocardial infarction, renal replacement, …) from baseline to W48","definition_or_measurement_approach":"Cumulative incidence of specified non-infectious complications from baseline to week 48."}
• {"endpoint_text":"- Variation of gammaglobulin and of CD19+ B cells levels from baseline to W12, W24 and W48","definition_or_measurement_approach":"Laboratory measurement of gammaglobulin and CD19+ B cell counts at baseline and weeks 12, 24 and 48."}
• {"endpoint_text":"- Overall survival, from baseline to the end of follow-up","definition_or_measurement_approach":"Overall survival measured from baseline to end of follow-up."}

France

Earliest CTIS Part Ii Submission Date

15-09-2025

Latest Decision Or Authorization Date

02-10-2025

Processing Time Days

17

Number Of Sites

25

Number Of Participants

30

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France