Clinical trial NCT06940661: Obinutuzumab for Remission Induction in Patients With Relapsing PR3-ANCA Granulomatosis With Polyangiitis
Official title: Obinutuzumab for Remission Induction in Patients With Relapsing PR3-ANCA Granulomatosis With Polyangiitis (Wegener's). Phase 2 Prospective, Open-label Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Granulomatosis With Polyangiitis
Keywords: Relapsing PR3-ANCA granulomatosis with polyangiitis
Obinutuzumab
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2025-04-23
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of obinutuzumab to induce clinical and serological remission in patients with relapsing PR3-ANCA granulomatosis with polyangiitis.

Detailed description: Systemic vasculitides are rare inflammatory diseases of blood vessels, among which anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are one of the most severe forms with life-threatening manifestations. In patients with AAV, the most important questions are how to achieve a long-term remission and prevent a relapse most effectively.

The pivotal RAVE trial showed that rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in AAV; and could be superior than cyclophoshamide in proteinase 3 (PR3)-ANCA patients. The MAINRITSAN trial, conducted by our group (Groupe Français d'Etude des Vascularites), has then demonstrated that more AAV patients had sustained remission with rituximab than with azathioprine.

However, despite its ability to induce and maintain remission, rituximab is associated with the occurrence of relapse after discontinuation in up to 50% of patients at 5-years in PR3-ANCA patients. Data strongly suggest that achieving clinical and serological remission (i.e. a BVAS (Birmingham Vasculitis Activity Score) of 0 and a negativation of ANCA) and longer B-cell depletion could be major goals to achieve in PR3-ANCA granulomatosis with polyangiitis to decrease the risk of relapse.

Obinutuzumab is a humanized type 2 antibody targeted against CD20. In preclinical studies, obinutuzumab showed superior efficacy, as compared with rituximab. In clinical studies, obinutuzumab was shown to be superior to rituximab in patients with chronic lymphocytic leukemia and follicular lymphoma, and met its primary and secondary endpoints in lupus nephritis.

The OBI-WAN study aims to evaluate the efficacy and safety of obinutuzumab to induce clinical and serological remission in patients with relapsing PR3-ANCA granulomatosis with polyangiitis. We hypothesize that obinutuzumab would induce higher remission rates and subsequent longer B-cell depletion compared to what is described for rituximab.

Eligibility criteria: Inclusion Criteria:

* Patient aged of 18 years or older,
* Patients with relapsing granulomatosis with polyangiitis positive for PR3-ANCA (at initial diagnosis or during follow-up), according to the ACR/EULAR 2022 classification criteria, and/or the 2012 revised Chapel Hill Consensus Conference definition.
* Patients with an active disease defined as a Birmingham Vasculitis Activity Score (BVAS) ≥ 3,
* Patients within the first 21 days following initiation/increase of glucocorticoids at a dose ≤1 mg/kg/day (pulses of methylprednisolone before oral glucocorticoid therapy are authorized)
* Patient able to give written informed consent prior to participation in the study, - Affiliation with a mode of social security (profit or being entitled).

Exclusion Criteria

* Patients with MPO-positive AAV, or other vasculitis, defined by the ACR criteria and/or the Chapel Hill Consensus Conference,
* Patients with vasculitis in remission of the disease defined as a BVAS \< 3,
* Patients with a newly-diagnosis of GPA
* Patients treated with rituximab within the last 6 months before inclusion
* Patients treated with cyclophosphamide within the last 6 months before inclusion
* Patients with severe cardiac failure defined as class IV in New York Heart Association
* Subject known to be seropositive for human immunodeficiency virus (HIV), hepatitis B (included history of previous infection) or hepatitis C
* Patients with active cancer or recent cancer (\< 5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment,
* Patients with hypersensitivity to a monoclonal antibody or biologic agent,
* Patients with hypersensitivity to obinutuzumab or to its excipients
* Contra-indications to auxiliary medicinal products (methylprednisolone, paracetamol, prednisone, dexchlorpheniramine)
* Patients with other uncontrolled diseases, including drug or alcohol abuse, active infections or antecedents of chronic or recurrent infections, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
* Patients suspected not to be observant to the proposed treatments,
* Pregnant women and lactation. All women of childbearing potential (WOCBP) are required to have a negative pregnancy test (blood or urine) 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 through the end of the study, and at least 18 months after stopping obinutuzumab such as 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,
* Men who refuse to use effective method of contraception (condom) from the date of consent through the end of the study and at least 18 months after stopping obinutuzumab (unless permanently sterile by bilateral orchidectomy or vasectomy),
* Patient participating in another investigational therapeutic study
* Protected adults (including individual under legal guardianship by court order or curatorship) or adults deprived of liberty
* Patients unable to give written informed consent prior to participation in the study.
* Patients with severe liver insufficiency (prothrombin time \<50% and total bilirubin \>50 micrmol/L)) or pulmonary insufficiency requiring nasal oxygen,
* Patients with an active infection or a history of chronic or recurrent infections
* Vaccination with live virus vaccines in the 4 weeks before study enrolment

Primary outcomes:
measure: the percentage of patients who achieved clinical and serological remission at week 24 (month 6)
timeFrame: week 24
Secondary outcomes:
measure: Proportion of participants experiencing adverse events and severe adverse events
timeFrame: Week 24 and 52
measure: Number and causes of deaths
timeFrame: Week 52
measure: Proportion of disease flares, including minor and major relapses
timeFrame: Week 52
measure: Proportion of participants who remain with a BVAS of 0 during the treatment period with prednisone at a dose of less than 10 mg per day
timeFrame: Treatment period
measure: The time to B-cell repopulation defined by detectable CD19+ B cells in peripheral blood over the 12 months study period
timeFrame: Week 24 and 52
measure: The patient-reported outcomes (PRO) including HAQ and SF-36, patient-reported disease activity at week 24 and 52
timeFrame: Week 24 and 52
measure: The Vasculitis Damage Index at week 24 and 52
timeFrame: Week 24 and 52
Other outcomes:
Locations:
city: Paris
country: France
facility: Service de Médecine Interne, Centre de reference "Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques"
Study officials:
affiliation: Hôpital Cochin, Assistance Publique-Hôpitaux de Paris - Service de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "
name: Xavier PUECHAL, PhD
role: STUDY_DIRECTOR
References: