Search

Background. Sequential B cell targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) and may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Study Design. COMBIVAS is a randomised, double blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3-AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per protocol analysis. Thirty-six participants have been randomised to one of two treatment groups in a 1:1 ratio; either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen) and recruitment is now closed (final patient enrolled March 2021). For each patient, the trial will last for two years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants. Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ³18 years, a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3-ANCA by ELISA. Interventions. Rituximab 1000mg was administered by intravenous infusions on Day 8 and Day 22. Weekly subcutaneous injections of 200mg belimumab or placebo were initiated a week before rituximab on Day 1 and then weekly through to Week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from Day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes. The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in blood at Months 3, 12, 18 and 24, time to clinical remission, time to relapse, and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and Month 3. Discussion. This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial status. The final patient was recruited in March 2021. Last subject last visit will be March 2023. ClinicalTrials.gov Identifier: NCT03967925, May 30, 2019.

ObjectiveFollowing induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.MethodsRITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).ResultsRituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, pConclusionsFollowing induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.Trial registration numberNCT01697267; ClinicalTrials.gov identifier