Efficacy and Safety of Obinutuzumab in Non-Infectious Active Cryoglobulinemia Vasculitis Refractory or Intolerant to Rituximab: A Phase 2 Study

Primary objective: to evaluate the efficacy of obinutuzumab in patients with non‑infectious active cryoglobulinemia vasculitis who are refractory or intolerant to rituximab, thereby addressing the clinical need for an alternative B‑cell‑depleting strategy when rituximab fails.

• Assessment of safety and tolerability of the treatment
• Assessment of overall clinical response
• Assessment of renal response
• Assessment of cryoglobulinemia levels
• Assessment of rheumatoid factor activity
• Assessment of C4 complement level
• Assessment of early treatment failure
• Assessment of incidence of clinical relapse (severe and non‑severe)
• Assessment of incidence of severe clinical relapse
• Assessment of incidence of mild or moderate relapse
• Assessment of corticosteroid‑sparing effect
• Assessment of Birmingham Vasculitis Activity Score (BVAS)
• Assessment of quality of life
• Assessment of incidence of infections (overall, severe, and non‑severe)
• Assessment of incidence of non‑infectious complications
• Evaluation of gammaglobulin and CD19+ B‑cell level dynamics
• Assessment of overall survival

The trial enrolled adult individuals of both sexes who met the definition of non-infectious active cryoglobulinemia vasculitis and were either refractory to or intolerant of rituximab; the sponsor did not provide the total number of participants. Eligible participants were required to be aged 18 years or older, have documented active disease involving one or more organ systems (e.g., skin, joint, renal, neurological, gastrointestinal, pulmonary, or cardiac), and demonstrate serologic evidence such as positive cryoglobulins, rheumatoid factor with low C4 complement, or an IgM‑kappa monoclonal component. Key exclusion criteria included recent infection with HIV, hepatitis B (positive HBsAg), or hepatitis C (positive HCV RNA), and lack of affiliation with the French national social security system. The population thus comprised a mixed cohort of male and female patients across the age ranges indicated by the study’s coding system, all presenting with active vasculitic disease and meeting the specified laboratory and clinical thresholds.

The CRYOBI study is a multicenter phase 2 single‑arm proof‑of‑concept trial evaluating the efficacy and safety of a single intravenous dose of Obinutuzumab (1000 mg) in adult patients with non‑infectious active cryoglobulinemia vasculitis who are refractory or intolerant to rituximab. After obtaining written informed consent, eligible participants undergo a screening visit to confirm inclusion criteria, followed by a baseline visit in which the study drug is administered. Subsequent study visits are scheduled at weeks 4, 12, 24 and 48 for clinical assessment, laboratory testing, and evaluation of corticosteroid use. The primary endpoint, complete clinical response at 6 months, and multiple secondary endpoints are measured throughout the follow‑up period. Participants remain in the study for approximately 48 weeks, with the final end‑of‑study visit occurring at week 48. Early termination may occur for lack of clinical response at week 4, occurrence of a severe adverse event, withdrawal of consent, or protocol‑defined contraindications. The overall trial duration, including recruitment, spans from October 2025 to July 2028.

The investigational product is Gazyvaro 1,000 mg concentrate for solution for infusion, containing the monoclonal antibody obinutuzumab. The formulation is a sterile solution for infusion intended for intravenous administration. The specified dose is 1,000 mg per infusion, delivered through a peripheral or central venous line according to standard infusion procedures.

No additional experimental agents are administered in this study. Patients may receive concomitant standard‑of‑care therapies as required for the management of cryoglobulinemic vasculitis, but no placebo or comparator drug is provided.

All infusions are performed in a clinical setting by qualified personnel. Dosing schedules, including the number of infusions and intervals between them, follow the protocol-defined schema. Compliance with the infusion regimen is monitored by recording infusion start and end times, dose administered, and any infusion‑related adverse events in the study case report forms.

Efficacy will be primarily evaluated by the proportion of patients achieving a complete clinical response of cryoglobulinemia vasculitis at six months. Complete remission is defined as resolution of all organ manifestations present at baseline together with withdrawal of corticosteroids and the absence of severe clinical relapse.

Secondary efficacy assessments will be performed at baseline and at weeks 4, 12, 24, and 48. The following parameters will be measured:

• Frequency and severity of adverse clinical events.
• Rates of complete clinical response with prednisone withdrawal (0 mg/day), partial response, and no clinical response.
• Renal remission, defined by proteinuria < 0.5 g/24 h or proteinuria/creatininuria < 50 mg/mmol and an improvement in glomerular filtration rate of >20 % when baseline GFR < 60 mL/min/1.73 m², or maintenance of GFR > 60 mL/min/1.73 m².
• Absence of detectable cryoglobulins.
• Absence of rheumatoid factor activity.
• Normalization of C4 complement levels.
• Early treatment failure, defined as lack of clinical response at week 4.
• Cumulative incidence of clinical relapse (severe, mild or moderate) from baseline to the end of follow‑up.
• Cumulative prednisone dose at weeks 24 and 48.
• Variation in the BVAS activity score from baseline to weeks 12, 24 and 48.
• Change in the physical and mental summary components of the SF‑36 questionnaire from baseline to weeks 24 and 48.
• Cumulative incidence of infections (overall, severe, non‑severe) and non‑infectious complications (cancer, lymphoma, cardiovascular events, renal replacement, etc.) from baseline to week 48.
• Changes in gammaglobulin levels and CD19+ B‑cell counts from baseline to weeks 12, 24 and 48.
• Overall survival from baseline to the end of follow‑up.

Clinical assessments will utilize validated scales (BVAS, SF‑36) and laboratory investigations for proteinuria, creatininuria, complement C4, rheumatoid factor, cryoglobulin quantification, gammaglobulin concentrations, and flow cytometric enumeration of CD19+ B‑cells. Data will be collected at the specified visits, analyzed according to predefined statistical plans, and compared with baseline values to determine treatment efficacy.