COMBIVAS.

Study name	A Randomised, Double Blind, Controlled Mechanistic Study of Rituximab and Belimumab Combination Therapy in PR3 ANCA‐associated Vasculitis
Methods	A phase II randomised, double‐blind, multi‐centre study with two arms: 1. arm: 200 mg belimumab with rituximab 2. arm: rituximab with placebo administered by subcutaneous injection once a week
Participants	nclusion Criteria: Participants ≥ 18 years old. Active disease of granulomatosis with polyangiitis or microscopic polyangiitis defined by one major or three minor items on BVAS/WG. Proteinase 3 ANCA detected by ELISA at screening. Informed consent. Exclusion Criteria: At screening: Positive for Myeloperoxidase (MPO)‐ANCA or anti‐glomerular basement membrane antibody detected by ELISA. Lung haemorrhage with hypoxia. Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2. Acute serious or chronic infection. Patients with undetectable peripheral blood B cells. Patients with Immunoglobulin G < 400mg/dl Previous treatment before Day 1: Any B cell targeted therapy within 364 days, Cyclophosphamide within 180 days, Any steroid injection within 60 days (unless provided during or 14 days before screening period) Methylprednisolone (IV) >1.5mg between 14 days prior to screening and Day 1 (including Day 1). 8. Prednisolone on average >10mg/day (or equivalent) orally during 30 days prior to screening.
Interventions	Arm 1 Belimumab (Benlysta) 200 mg administered by subcutaneous injection once a week for 12 months co‐administration of rituximab Arm 2 Placebo administered by subcutaneus injection once a week for 12 months. co‐administration of rituximab
Outcomes	Major outcome measures: Time to PR3 ANCA negativity ‐ ELISA analysis at different time points to determine when PR3 ANCA can no longer be detected. Minor outcomes measures: Percentage of participants with PR3 ANCA negativity ‐ measured by ELISA at various time points. Change from baseline of certain cell subsets ‐ measured by flow cytometry at various time points. Time to clinical remission ‐ measured by BVAS/WG. Incidence of serious AEs (SAEs) ‐ hospitalisation or serious events.
Starting date	February 2019
Contact information	Kim Mynard 01223 349350 kim.mynard@addenbrookes.nhs.uk Principal Investigator: Rachel Jones
Notes	Estimated Primary Completion Date: February 2022 (Final data collection date for major outcome measure) ClinicalTrials.gov Identifier: NCT03967925

AAV – Anti‐neutrophilic cytoplasmic antibodies (ANCA)‐associated vasculitis

AAVTCZ ‐ Clinical trial of tocilizumab versus cyclophosphamide for microscopic polyangiitis and granulomatosis with polyangiitis

ABROGATE ‐ Abatacept for the Treatment of Relapsing, Non‐Severe, Granulomatosis With Polyangiitis

ACR – American College of Rheumatology

AE – adverse event

ALEVIATE ‐ Alemtuzumab for ANCA Associated Refractory Vasculitis

ANCA – antineutrophil cytoplasmic antibody

anti‐MPO – anti‐myeloperoxidase

anti‐PR3 – Anti‐proteinase 3 ‐

BVAS – Birmingham Vasculitis Activity Score

BVAS/WG – Birmingham Vasculitis Activity Score for granulomatosis with polyangiitis

CDC – Centre for Disease Control

COMBIVAS ‐ A Randomised, Double Blind, Controlled Mechanistic Study of Rituximab and Belimumab Combination Therapy in PR3 ANCA‐associated Vasculitis

CS – corticosteroid

DNA – deoxyribonucleic acid

eGFR – Estimated glomerular filtration rate

EGPA – eosinophilic granulomatosis with polyangiitis

ELISA – enzyme‐bound immunosorbent analysis

EQ5D – The EuroQol (European Quality of Life) Five Dimension Scale

EUVAS ‐ European Vasculitis Study Group

GPA – granulomatosis with polyangiitis

HB ‐ hepatitis B

HBV ‐ hepatitis B virus

HIV – human immunodeficiency virus

IV – intravenous

IVCY – intravenous cyclophosphamide

Kg – kilogram

MCP‐1 – monocyte chemoattractant protein‐1

MPA – microscopic polyangiitis

PSL ‐ prednisolone

SAE – serious adverse event

SF‐36 – Short Form‐36

TCZ – tocilizumab