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

NCT07268521 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: APHP230848
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Cryoglobulinemic Vasculitis (CV)

Keywords

Cryoglobulinemic vasculitis (CV)

Outcome Measures

Primary Outcomes (1)

• Complete Clinical Response

  Remission of all affected organs involved at baseline and with corticosteroid withdrawal in the absence of severe clinical relapse

  At 6 months

Secondary Outcomes (41)

• Frequency of adverse clinical events

  At 12 weeks

• Frequency of adverse clinical events

  At 24 weeks

• Frequency of adverse clinical events

  At 48 weeks

• Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response

  At 12 weeks

• Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response

  At 24 weeks

Study Arms (1)

Adult patients with non-infectious active cryoglobulinemia vasculitis

EXPERIMENTAL

Drug: Obinutuzumab

Interventions

Obinutuzumab DRUG

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

Adult patients with non-infectious active cryoglobulinemia vasculitis

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• Vasculitis unrelated to cryoglobulinemia
• Non-active cryoglobulinemia vasculitis
• 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.
• 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
• Patients under guardianship or curatorship and protected adults or unable to consent
• Progressive multifocal leukoencephalopathy
• Participation to another interventional study

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

Cryoglobulinemia, Familial Mixed

Interventions

obinutuzumab

Central Study Contacts

David Saadoun, MD PhD

CONTACT

+33 (0)1 42 17 80 42; david.saadoun@aphp.fr

Jérôme Lambert, MD PhD

CONTACT

jerome.lambert@u-paris.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: multicenter open pilot phase 2 single arm prospective study

Study Record Dates

• First Submitted: November 18, 2025
• First Posted: December 5, 2025
• Study Start: December 1, 2025
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: December 5, 2025

Record last verified: 2025-11