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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
Patient will receive 1000 milligrams intravenous (IV) infusion on week 0, week 2, week 24 and week 26. Patients will receive the same standardized glucocorticoid tapering schedule (prescribe as a standard of care management and considered as auxiliary medicinal product) Premedication for obinutuzumab infusion related reactions (considered as auxiliary medicinal products) : * 100 mg methylpredinisolone * 1000 mg paracetamol * 5 mg dexchlorpheniramine
Service de Médecine Interne, Centre de reference "Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques"
Paris, France
RECRUITINGthe percentage of patients who achieved clinical and serological remission at week 24 (month 6)
The percentage of patients who achieved clinical and serological remission at week 24 (month 6), defined by: * a BVAS of 0, * a negativation of PR3-ANCA, * and successful completion of the prednisone taper
Time frame: week 24
Proportion of participants experiencing adverse events and severe adverse events
The number of adverse events, expressed as adverse events according to the CTCAE toxicity grading system per patient-year at week 24 and 52 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, haemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions,
Time frame: Week 24 and 52
Number and causes of deaths
Number and causes of deaths
Time frame: Week 52
Proportion of disease flares, including minor and major relapses
Proportion of participants who had vasculitis relapses (BVAS \> 0), including minor and major relapses over the 12 months study periodCD19
Time frame: Week 52
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
BVAS, prednisone dose
Time frame: Treatment period
The time to B-cell repopulation defined by detectable CD19+ B cells in peripheral blood over the 12 months study period
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CD19+ rate
Time frame: Week 24 and 52
The patient-reported outcomes (PRO) including HAQ and SF-36, patient-reported disease activity at week 24 and 52
HAQ and SF-36 questionnaires
Time frame: Week 24 and 52
The Vasculitis Damage Index at week 24 and 52
Vasculitis Damage Index (VDI)
Time frame: Week 24 and 52