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

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

30 Jan 2026 → ongoing

Decision date (initial)

2025-10-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

To assess the efficacy of Obinutuzumab in patients with non-infectious active CV refractory or intolerant to Rituximab

Secondary objectives 19

1. Assessment of safety and tolerability of the treatment
2. Assessment of overall clinical response
3. Assessment of renal response
4. Assessment of cryoglobulinemia
5. Assessment of rheumatoid factor activity
6. Assessment of C4 complement level
7. Assessment of early treatment failure
8. Assessment of incidence of clinical relapse (severe and non-severe)
9. Assessment of incidence of severe clinical relapse
10. Assessment of incidence of mild or moderate relapse
11. Assessment of corticosteroids sparing
12. Assessment of birmingham Vasculitis Activity Score (BVAS)
13. Assessment of quality of life
14. Assessment of incidence of infections (severe or not)
15. Assessment of incidence of severe infections
16. Assessment of incidence of non-severe infections
17. Assessment of incidence of non-infectious complications
18. Evolution of gammaglobulin and of CD19+ B cells levels
19. Assessment of overall survival

Conditions and MedDRA coding

Non-infectious active cryoglobulinemia vasculitis who are either refractory or intolerant to Rituximab

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age ≥ 18 years
2. Written informed consent
3. 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
4. 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: - 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.
5. HIV negative serology within 3 months prior inclusion
6. Negative HBs Ag test. within 3 months prior inclusion
7. HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion
8. 8. Affiliated to National French social security system (registered or being a beneficiary of such a scheme). Patients with AME are eligible.

Exclusion criteria 14

1. Vasculitis unrelated to cryoglobulinemia
2. Live vaccines within 30 days prior inclusion
3. Patients under guardianship or curatorship and protected adults or unable to consent
4. Progressive multifocal leukoencephalopathy
5. Participation to another interventional study
6. Non-active cryoglobulinemia vasculitis
7. Treatment with cyclophosphamide or Belimumab within 3 months prior to inclusion
8. 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.
9. Active tuberculosis, pneumocystis, cytomegalovirus or any active infection not adequately managed or considered a risk by the investigator
10. Have a history of an anaphylactic reaction to parenteral administration of Obitunuzumab
11. Pregnant or breastfeeding women, or desire to become pregnant within 30 months
12. 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
13. Neutrophils < 1000/mm3 or Platelets < 50000/mm3
14. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 19

1. Frequency and severity of adverse clinical events at W12, W24 and W48
2. 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)
3. 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.
4. Rate of patients without cryoglobulinemia at W12, W24 and W48
5. Rate of patients without rheumatoid factor activity at W12, W24 and W48
6. Rate of patients with normal C4 complement level at W12, W24 and W48
7. Rate of patients with early treatment failure defined as the absence of clinical response at W4
8. 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
9. Cumulative incidence of severe clinical relapse from baseline to the end of follow-up
10. Cumulative incidence of mild or moderate clinical relapse from baseline to the end of follow up
11. Cumulative dose of prednisone at W24 and at W48.
12. BVAS activity score variation from baseline to W12, W24 and W48
13. Variation in physical and mental summary components of score SF-36 from baseline to W24 and to W48
14. Cumulative incidence of infections (severe or non-severe) from baseline to W48
15. Cumulative incidence of severe infections from baseline to W48
16. Cumulative incidence of non-severe infections from baseline to W48
17. Cumulative incidence of non-infectious complications (cancer, lymphoma, cardiovascular event: stroke, myocardial infarction, renal replacement, …) from baseline to W48
18. Variation of gammaglobulin and of CD19+ B cells levels from baseline to W12, W24 and W48
19. Overall survival, from baseline to the end of follow-up

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

David SAADOUN

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

David SAADOUN

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications