Cryoglobulinemic Vasculitis (CV)Phase 2CRYOBINCT07268521
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
A Phase 2 study testing Obinutuzumab in people with Cryoglobulinemic Vasculitis (CV), run by Assistance Publique - Hôpitaux de Paris at 25 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cryoglobulinemic Vasculitis (CV)
- What is being tested?
- Obinutuzumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 25 sitesFrance
- Study dates
- 30 Jan 2026to 30 Sep 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
25 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Jérôme Lambert, MD PhD contact
25 sites in 1 country
France25 sites, 25 recruiting
- Not yet recruiting
CH Blois
Blois
Bertrand Lioger, 0254556365 ext. +33, liogerb@ch-blois.fr
- Recruiting
Hôpital Jean Verdier
Bondy
Laurent Gilardin, 0148026361 ext. +33, laurent.giraldin@aphp.fr
- Recruiting
CHU Bordeaux
Bordeaux
Estibaliz Lazaro, 0557656483 ext. +33, estibaliz.lazaro@chu-bordeaux.fr
- Recruiting
CHU Caen
Caen
Achille Aouba, 0231064479 ext. +33, achille.aouba@gmail.com
- Recruiting
CHU Clermont-Ferrand
Clermont-Ferrand
Marc André, 0473751435 ext. +33, mandre@chu-clermontferrand.fr
- Recruiting
Hôpital Henri Mondor AP-HP
Créteil
Joher Nizar, 0149814456 ext. +33, nizar.joher@aphp.fr
- Recruiting
CHU Dijon
Dijon
Maxime Samson, 0426732631 ext. +33, maxime.samson@chu-dijon.fr
- Recruiting
Hôpital Bicêtre AP-HP
Le Kremlin-Bicêtre
Gaétane Nocturne, 0145213758 ext. +33, gaetane.nocturne@aphp.fr
- Recruiting
CH Le Mans
Le Mans
Paul Legendre, 0243432485 ext. +33, plegendre@ch-lemans.fr
- Recruiting
CHRU Lille
Lille
David Launay, 0320444296 ext. +33, david.launay@chru-lille.fr
- Recruiting
CHU Lyon
Lyon
Yvan Jamilloux, 0426732631 ext. +33, yvan.jamillou@chu-lyon.fr
- Recruiting
AP-HM
Marseille
Gilles Kaplanski, 0491383501 ext. +33, gilles.kaplanski@ap-hm.fr
- Recruiting
GHSIF Melun
Melun
Nabil Belfeki, 0181742075 ext. +33, nabil.belfeki@ghsif.fr
- Recruiting
CHU Nantes
Nantes
Antoine Neel, 0240087765 ext. +33, antoine.neel@chu-nantes.fr
- Recruiting
CHU Nîmes
Nîmes
Olivier Moranne, 0466683256 ext. +33, olivier.moranne@chu-nimes.fr
- Recruiting
Hôpital Bichat AP-HP
Paris
Antoine Dossier, 0140255302 ext. +33, antoine.dossier@aphp.fr
- Recruiting
Hôpital de La Pitié Salpetrière
Paris
David Saadoun, 0142178009 ext. +33, david.saadoun@aphp.fr
- Recruiting
Hôpital Lariboisière
Paris
Chloé Comarmond Ortoli, 0149956321 ext. +33, chloe.comarmondortoli@aphp.fr
- Recruiting
Hôpital Necker AP-HP
Paris
Aurélie Hummel, 0146682511 ext. +33, aurelie.hummel@aphp.fr
- Recruiting
Hôpital Saint Louis AP-HP
Paris
Baptiste Hervier, 0142499769 ext. +33, baptiste.hervier@aphp.fr
- Recruiting
CHRU Strasbourg
Strasbourg
Jacques-Eric Gottenberg, 0388128015 ext. +33, jacques-eric.gottenberg@chru-strasbourg.fr
- Recruiting
Hôpital Foch
Suresnes
Felix Ackermann, 0146252620 ext. +33, f.ackermann@hopital-foch.com
- Recruiting
CHU Toulouse
Toulouse
Stanislas Faguer, 0561323288 ext. +33, stanislas.faguer@inserm.fr
- Recruiting
CHU Tours
Tours
Alexandra Audemard, 0247473715 ext. +33, alexandra.audemardverger@univ-tours.fr
- Not yet recruiting
CH Valenciennes
Valenciennes
Clémentine Rousselin, 0327145077 ext. +33, rousselin-c@ch-valenciennes.fr
About this study
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)
- Being tested
- Obinutuzumab
- Keywords
- Cryoglobulinemic vasculitis (CV)
- Medical subject headings
- Cryoglobulinemia, Familial Mixed
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ObinutuzumabDrug
Obinutuzumab will be administered intravenously at 1000 milligrams (mg) at week 0 and week 2
| Study group | Role | What they receive |
|---|---|---|
| Adult patients with non-infectious active cryoglobulinemia vasculitis | Experimental | Not described Receives: Drug: Obinutuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete Clinical Response
Remission of all affected organs involved at baseline and with corticosteroid withdrawal in the absence of severe clinical relapse
Measured: At 6 months
Secondary outcomes (41)
Frequency of adverse clinical events
Frequency and severity of adverse clinical events
Measured: At 12 weeks
Frequency of adverse clinical events
Frequency and severity of adverse clinical events
Measured: At 24 weeks
Frequency of adverse clinical events
Frequency and severity of adverse clinical events
Measured: At 48 weeks
Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response
Measured: At 12 weeks
Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response
Measured: At 24 weeks
Rates of patients with complete clinical response with corticosteroid withdrawal (prednisone at 0 mg/day), partial response, and no clinical response
Measured: At 48 weeks
Rate of patients with complete renal remission
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/1.73m² if GFR ≥ 60ml/min/1.73m² at diagnosis.
Measured: At 12 weeks
Rate of patients with complete renal remission
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/1.73m² if GFR ≥ 60ml/min/1.73m² at diagnosis.
Measured: At 24 weeks
Rate of patients with complete renal remission
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/1.73m² if GFR ≥ 60ml/min/1.73m² at diagnosis.
Measured: At 48 weeks
Rate of patients without cryoglobulinemia
Measured: At 12 weeks
Rate of patients without cryoglobulinemia
Measured: At 24 weeks
Rate of patients without cryoglobulinemia
Measured: At 48 weeks
Rate of patients without rheumatoid factor activity
Measured: At 12 weeks
Rate of patients without rheumatoid factor activity
Measured: At 24 weeks
Rate of patients without rheumatoid factor activity
Measured: At 48 weeks
Rate of patients with normal C4 complement level
Measured: At week 12
Rate of patients with normal C4 complement level
Measured: At week 24
Rate of patients with normal C4 complement level
Measured: At week 48
Rate of patients with early treatment failure
Defined as the absence of clinical response
Measured: At week 4
Cumulative incidence of clinical relapse (severe or non-severe)
Defined by reappearance of a manifestation attributable to cryoglobulinemia vasculitis
Measured: Up to 144 weeks
Cumulative incidence of severe clinical relapse
A severe relapse is defined by the appearance or reappearance of one of the following signs:
- Extensive skin necrosis with loss of substance
- Specific cardiac involvement of vasculitis (documented by EKG, troponin and/or MRI)
- Specific digestive impairment of vasculitis (documented by imaging and/or endoscopy)
- Affection of the central nervous system specific to vasculitis (documented by cerebral MRI)
- Multiple mononeuropathy clinically defined by asymmetrical motor impairment of 2 or more nerve trunks. (Documented by electromyogram)
- Severe renal impairment defined as a doubling of creatinine levels from the usual value or a glomerular filtration rate according to CKD-EPI of less than 30 ml/min/1.73m2 in the absence of prior history of creatinine levels)
Measured: Up to 144 weeks
Cumulative incidence of mild or moderate clinical relapse
- Appearance or reappearance of purpura
- Arthritis
- Sensory neuropathy documented by electromyogram
- Glomerulonephritis (proteinuria>1g/24h after excluding other causes of proteinuria)
Measured: Up to 144 weeks
Cumulative dose of prednisone
Measured: At week 24
Cumulative dose of prednisone
Measured: At 48 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Standardized clinical tool used to quantify disease activity. It varies from 0 to 63. The higher the BVAS, the more active and severe the vasculitis.
Variation assessed from baseline
Measured: Up to 12 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Standardized clinical tool used to quantify disease activity. It varies from 0 to 63. The higher the BVAS, the more active and severe the vasculitis.
Variation assessed from baseline
Measured: Up to 24 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Standardized clinical tool used to quantify disease activity. It varies from 0 to 63. The higher the BVAS, the more active and severe the vasculitis.
Variation assessed from baseline
Measured: Up to 48 weeks
Variation in physical summary components of score SF-36
SF-36 assesses overall health-related quality of life across multiple domains. Each domain is scored from 0 to 100. 0 = worst possible health status 100 = best possible health status It is assessed from baseline.
Measured: Up to 24 weeks
Variation in physical summary components of score SF-36
SF-36 assesses overall health-related quality of life across multiple domains. Each domain is scored from 0 to 100. 0 = worst possible health status 100 = best possible health status It is assessed from baseline.
Measured: Up to 48 weeks
Variation in mental summary components of score SF-36
SF-36 assesses overall health-related quality of life across multiple domains. Each domain is scored from 0 to 100. 0 = worst possible health status 100 = best possible health status It is assessed from baseline.
Measured: Up to 24 weeks
Variation in mental summary components of score SF-36
SF-36 assesses overall health-related quality of life across multiple domains. Each domain is scored from 0 to 100. 0 = worst possible health status 100 = best possible health status It is assessed from baseline.
Measured: Up to 48 weeks
Cumulative incidence of infections (severe or non-severe)
From baseline
Measured: Up to 48 weeks
Cumulative incidence of severe infections
From baseline
Severe infection defined by:
- Tuberculosis, pneumocystis, or cytomegalovirus,
- Leading to hospitalization
- Leading to life threatening or death
- Progressive multifocal leukoencephalopathy.
- If PML is confirmed, study agent should be discontinued and consideration should be given to stopping immunosuppressant therapy.
- Neoplasia
- Serious Hypersensitivity or Infusion Reactions ≥ grade 3 CTCAE
- Clinically significant, potentially life-threatening (Grade 4) adverse event (AE) that the investigator believes is definitely, possibly or probably related to study agent.
Measured: Up to 48 weeks
Cumulative incidence of non-severe infections
From baseline Infections that do not meet the definition of a "severe infection"
Measured: Up to 48 weeks
Cumulative incidence of non-infectious complications (cancer, lymphoma, cardiovascular event: stroke, myocardial infarction, renal replacement, …)
From baseline
Measured: Up to 48 weeks
Variation of gammaglobulin and of CD19+ B cells levels
From baseline
Measured: Up to 12 weeks
Variation of gammaglobulin levels
From baseline
Measured: Up to 24 weeks
Variation of gammaglobulin levels
From baseline
Measured: Up to 48 weeks
Overall survival
From baseline
Measured: Up to 144 weeks
Variation of CD19+ B cells levels
From baseline
Measured: Up to 24 weeks
Variation of CD19+ B cells levels
From baseline
Measured: Up to 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2025
- Study start30 Jan 2026
- Primary completion31 May 2028 (estimated)
- Study completion30 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cryoglobulinemic Vasculitis (CV)Studies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- multicenter open pilot phase 2 single arm prospective study
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07268521
- Sponsor's protocol ID
- APHP230848
- Acronym
- CRYOBI
- Status last verified
- Aug 2026
- First submitted
- 18 Nov 2025
- Last updated
- 31 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07268521
- Acronym / sponsor ID
- CRYOBI / APHP230848
- Conditions
- Cryoglobulinemic Vasculitis (CV)
- Keywords
- Cryoglobulinemic vasculitis (CV)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 30 Jan 2026 (actual)
- Primary completion
- 31 May 2028 (estimated)
- Study completion
- 30 Sep 2028 (estimated)
- First posted
- 5 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- multicenter open pilot phase 2 single arm prospective study
| Arm | Type | Receives |
|---|---|---|
| Adult patients with non-infectious active cryoglobulinemia vasculitis | Experimental | Drug: Obinutuzumab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- Age ≥ 18 years
- Written informed consent
- Active mixed cryoglobulinemia vasculitis defined by:
- 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):
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ObinutuzumabObinutuzumab will be administered intravenously at 1000 milligrams (mg) at week 0 and week 2 | Drug | Adult patients with non-infectious active cryoglobulinemia vasculitis |
Primary outcome
Complete Clinical Response
Time frame: At 6 months
Remission of all affected organs involved at baseline and with corticosteroid withdrawal in the absence of severe clinical relapse
41 secondary outcomes
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
Rate of patients without rheumatoid factor activity
Time frame: At 12 weeks
Rate of patients without rheumatoid factor activity
Time frame: At 24 weeks
Rate of patients without rheumatoid factor activity
Time frame: At 48 weeks
Rate of patients with normal C4 complement level
Time frame: At week 12
Rate of patients with normal C4 complement level
Time frame: At week 24
Rate of patients with normal C4 complement level
Time frame: At week 48
Rate of patients with early treatment failure
Time frame: At week 4
Cumulative incidence of clinical relapse (severe or non-severe)
Time frame: Up to 144 weeks
Cumulative incidence of severe clinical relapse
Time frame: Up to 144 weeks
Cumulative incidence of mild or moderate clinical relapse
Time frame: Up to 144 weeks
Cumulative dose of prednisone
Time frame: At week 24
Cumulative dose of prednisone
Time frame: At 48 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Time frame: Up to 12 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Time frame: Up to 24 weeks
Birmingham Vasculitis Activity Score (BVAS) activity score variation
Time frame: Up to 48 weeks
Variation in physical summary components of score SF-36
Time frame: Up to 24 weeks
Variation in physical summary components of score SF-36
Time frame: Up to 48 weeks
Variation in mental summary components of score SF-36
Time frame: Up to 24 weeks
Variation in mental summary components of score SF-36
Time frame: Up to 48 weeks
Cumulative incidence of infections (severe or non-severe)
Time frame: Up to 48 weeks
Cumulative incidence of severe infections
Time frame: Up to 48 weeks
Cumulative incidence of non-severe infections
Time frame: Up to 48 weeks
Cumulative incidence of non-infectious complications (cancer, lymphoma, cardiovascular event: stroke, myocardial infarction, renal replacement, …)
Time frame: Up to 48 weeks
Variation of gammaglobulin and of CD19+ B cells levels
Time frame: Up to 12 weeks
Variation of gammaglobulin levels
Time frame: Up to 24 weeks
Variation of gammaglobulin levels
Time frame: Up to 48 weeks
Overall survival
Time frame: Up to 144 weeks
Variation of CD19+ B cells levels
Time frame: Up to 24 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2026.
- Individual participant dataSharing planned: Undecided
Related trials for Cryoglobulinemic Vasculitis (CV)
RecruitingObservational study
Clinical Transcriptomics in Systemic Vasculitis (CUTIS)
Cryoglobulinemic Vasculitis (CV), Drug-induced Vasculitis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Jérôme Lambert, MD PhD contact
25 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Obinutuzumab in people with Cryoglobulinemic Vasculitis (CV), run by Assistance Publique - Hôpitaux de Paris at 25 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 31 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 25 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact David Saadoun, MD PhD (+33 (0)1 42 17 80 42 ext. +33, david.saadoun@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Complete Clinical Response (time frame: At 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2026.