A Multicenter Phase 2 Single-arm Proof-of-concept Trial Assessing the Efficacy and Safety of Obinutuzumab in the Treatment of Non-infectious Active Cryoglobulinemia Vasculitis Refractory or Intolerant to Rituximab

Overview

Cryoglobulinemic vasculitis (CV) is a rare life threatening systemic immune-complex-mediated vasculitic syndrome. Symptoms range from arthralgia, purpura to more severe manifestations such as peripheral neuropathy, glomerulonephritis, and skin necrosis.1 CV is associated with significant morbidity and mortality. The management of non-infectious mixed CV is currently based on steroids, and anti-CD20 monoclonal antibody Rituximab (RTX). Infectious complications of immunosuppressants (IS) remain the main cause of death in CV. During the last decade, studies reported efficacy of RTX in patients with CV in 65-70% of patients as compared to 30% for other IS (azathioprine…). However, CV relapse is noted in up to 40% patients within few days to 19 months after the last RTX infusion2. Following RTX, serum levels of B lymphocyte stimulator (BLyS) significantly increased and may favour the survival of autoreactive B cell clones and relapses of CV. A recent study has shown that RTX does not reset defective early B cell tolerance checkpoints. Incomplete B cell depletion following treatment with RTX may be associated with poor clinical response. Moreover, some patients develop a serum sickness reaction to RTX that contraindicate further use of the medication2. Thus, there are important therapeutic unmet needs in CV patients that are refractory or intolerant to RTX. Obinutuzumab (OBZ) is a type II anti-CD20 monoclonal antibody with a glycomodified Fc, approved in 2013 for the treatment of chronic lymphocytic leukemia. Reddy et al. found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in vitro whole blood assays of patients with rheumatoid arthritis and systemic lupus erythematosus. In lupus nephritis, OBZ resulted in increased complete and partial renal responses compared with placebo when added to mycophenolate mofetil and steroids for the treatment of lupus nephritis. There is a strong rationale for using OBZ in CV. OBZ is currently used off label in CV patients intolerant to RTX and case reports pointed out its effectiveness in CV4.5. CRYOBI is the first prospective multicenter phase 2 proof-of-concept trial assessing efficacy of OBZ in CV refractory or intolerant to RTX.

Interventions

• Drug Obinutuzumab
  Obinutuzumab will be administered intravenously at 1000 milligrams (mg) at week 0 and week 2

Primary outcome measures

• Complete Clinical Response [Time frame: At 6 months]

Secondary outcome measures (12)

• Frequency of adverse clinical events [Time frame: At 12 weeks]
• Frequency of adverse clinical events [Time frame: At 24 weeks]
• Frequency of adverse clinical events [Time frame: At 48 weeks]
• Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response [Time frame: At 12 weeks]
• Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response [Time frame: At 24 weeks]
• Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response [Time frame: At 48 weeks]
• Rate of patients with complete renal remission [Time frame: At 12 weeks]
• Rate of patients with complete renal remission [Time frame: At 24 weeks]
• Rate of patients with complete renal remission [Time frame: At 48 weeks]
• Rate of patients without cryoglobulinemia [Time frame: At 12 weeks]
• Rate of patients without cryoglobulinemia [Time frame: At 24 weeks]
• Rate of patients without cryoglobulinemia [Time frame: At 48 weeks]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Written informed consent
• 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
• 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):

• No measurable improvement within 4-6 weeks of initiation,
• OR <50% improvement in the number or severity of affected organ systems at 12 weeks, or
• OR 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:

"CRYOBI " protocol, version v1-2 of 26/08/2025 10/68 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 4.0 dated 31/05/2019

• The skin and articular remissions are evaluated clinically (disappearance of purpura and ulcers, disappearance of arthritis, disappearance of the skin necrosis).
• Renal 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
• Peripheral 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).
• Central 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)
• Digestive 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.
• Cardiac 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 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.

• HIV negative serology within 3 months prior inclusion
• Negative HBs Ag test within 3 months prior inclusion. (In case of negative AgHBs and positive HBc Ab test, HBV DNA test must be negative; AND Hepatitis B surveillance should be started (monthly HBsAg and HBV DNA testing for the duration of the study treatment and at least every 12 weeks after treatment is discontinued for the duration of study treatment. In addition, antiviral prophylaxis should be started before the first administration of the study treatment and continued until 12 months after completion of study treatment)
• HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion
• Affiliated to National French social security system (registered or being a beneficiary of such a scheme). Patients with AME are eligible

Exclusion criteria

• Vasculitis unrelated to cryoglobulinemia
• Non-active cryoglobulinemia vasculitis
• Treatment with cyclophosphamide or Belimumab within 3 months prior to inclusion
• 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.

"CRYOBI " protocol, version v1-2 of 26/08/2025 11/68 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 4.0 dated 31/05/2019 Carcinoma in situ of the cervix and squamous cell carcinoma of the skin should have been adequately treated before inclusion in the study.

• Active tuberculosis, pneumocystis, cytomegalovirus or any active infection not adequately managed or considered a risk by the investigator
• Have a history of an anaphylactic reaction to parenteral administration of Obitunuzumab
• 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
• Pregnant or breastfeeding women, or desire to become pregnant within 30 months 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
• Neutrophils < 1000/mm3 or Platelets < 50000/mm3
• Live vaccines within 30 days prior inclusion
• Patients under guardianship or curatorship and protected adults or unable to consent
• Progressive multifocal leukoencephalopathy
• Participation to another interventional study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07268521 · APHP230848

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗