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 mechanis (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 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 were recruited from 7 UK sites. Eligibility included age>18 years, severe active AAV (newly diagnosed or relapsing), and positive PR3 ANCA. Interventions: Belimumab (200mg) or belimumab placebo was administered subcutaneously on Day 1 and then weekly through to Week 51. Intravenous rituximab 1000mg was administered on Day 8 and Day 22 only. All participants started prednisolone 20 mg/day on Day 1 and followed a tapering regimen aiming for withawal 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 were 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 were performed on a subgroup of participants before and three months after initiating treatment for the purpose of exploratory analyses (including single cell RNA sequencing) examining the mechanistic effects of combination B cell depletion within tissues. Discussion: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanis of rituximab-belimumab combination therapy across multiple body compartments in the setting of AAV. Trial status - EUACT number: 2017-004645-24; Recruitment completed March 2021. Final study report due 2024. Disclosures: Rachel Jones has received grants/consultancy fees from GlaxoSmithKline, Vifor Pharma, ChemoCentryx and Roche. David Jayne’s disclosures of commercial conflicts for companies with marketed products for 2021 are: Astra-Zeneca, Aurinia, B, Boehringer-Ingelheim, GSK, Janssen, Novartis, Roche/Genentech, Takeda & Vifor.