322. A RANDOMISED, DOUBLE-BLIND, CONTROLLED, MECHANISTIC STUDY OF RITUXIMAB AND BELIMUMAB COMBINATION THERAPY IN PR3 ANCA-ASSOCIATED VASCULITIS (COMBIVAS): STUDY PROTOCOL

Abstract

Background: Dual B-cell targeted immunotherapy with B cell depletion (rituximab) and BAFF antagonism (belimumab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms (1). Study Design - COMBIVAS is a randomized, double blind, placebo-controlled trial designed to evaluate the mechanistic effect of belimumab combined with rituximab in patients with active proteinase 3 (PR3)-AAV. Participants will be S#sup#I#/sup#randomized 1:1 to receive rituximab plus prednisolone combined with belimumab (combination arm) or placebo (control arm). 30 participants will be evaluated in a per-protocol analysis. Trial duration is two years (12-months treatment, 12- months' follow-up). Participants - Participants will be recruited from 5 UK sites. Eligibility includes age>18 years, severe active AAV (newly diagnosed or relapsing), and positive PR3 ANCA test by enzyme-linked immunosorbent assay (ELISA). Interventions - Belimumab (200mg) or belimumab placebo will be administered subcutaneously on Day 1 and then weekly through to Week 51. Intravenous rituximab 1000mg will be administered on Day 8 and Day 22 only. All participants will start prednisolone 20 mg/day on Day 1 and follow a tapering regimen aiming for withdrawal by 3 months. Outcomes - Primary Outcome: Time to PR3-ANCA negativity; Key Secondary Outcomes: change from baseline in naïve, transitional, memory, activated, plasmablast and plasma cell subsets (B cell flow cytometry) in blood at Months 3, 12, and 24; time to clinical remission; time to relapse, incidence of serious adverse events. Exploratory biomarker assessments - Blood and urine will be taken at multiple time points, with key analyses at 3 months (maximal B cell depletion), 12 months (end of treatment), 24 months (B cell reconstitution, end of follow-up). Inguinal lymph node and nasal mucosal biopsies will be performed before and three months after initiating treatment. Discussion -This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of rituximab-belimumab combination therapy across multiple body compartments in the setting of AAV. Trial status - EUDRACT number: 2017-004645-24; First patient first visit: anticipated December 2018.