Title: Biologics in refractory vasculitis (BIOVAS): A pragmatic, randomised, double-blind, placebo-controlled, modified-crossover trial of biologic therapy for refractory vasculitis in adults and children.
Funder: Department of Health and Social Care

Abstract: Vasculitides, are rare autoimmune diseases causing organ damage due to blood vessel inflammation, affect all age groups and are treated with glucocorticoids with or without immunosuppressive drugs. Biologics are effective therapies of autoimmune vasculitis: rituximab (RTX) is licensed for ANCA vasculitis (AAV) and tocilizumab (TCZ) for giant cell arteritis (GCA). Biologics have been used off-label for non-AAV vasculitis (NAAV) for 15 years with several hundred observational reports of benefit. Patients with refractory disease have progressive incapacity, drug toxicity and accumulate high health costs. This proposal will test the clinical and cost-effectiveness of these biologics in patients with refractory NAAV. Trial design: A pragmatic, randomised, double-blind, placebo-controlled, modified-crossover trial of biologic therapy for refractory vasculitis in children and adults. Participants: 140 consenting adults and children with refractory NAAV (includes: GCA, Takayasu’s arteritis, polyarteritis nodosa, including cutaneous polyarteritis & DADA2, Cogan’s syndrome, cerebral vasculitis, relapsing polychondritis, IgA vasculitis, non-infective cryoglobulinaemic vasculitis). Key exclusions are: recent biologic exposure or change in immunosuppressive dosing, prior TB, chronic virus infection, pregnancy, and malignancy. Interventions: Patients are randomly allocated to a sequence of four agents-infliximab/TCZ/RTX/placebo and progress to the next agent in the sequence if they fail to remit by four months or relapse after remission. All interventions are given intravenously (IV) and follow standardised regimens. The placebo regimen is chosen randomly to mirror the infusion protocol for one of the biologics. Outcomes: Primary outcome: Time to treatment failure (TTF), assessed separately for each intervention aggregated across the total population. Secondary outcomes: disease activity scores, adult or paediatric equivalent patient-reported outcomes, physician’s global assessment, health-related quality of life, cumulative steroid dose and toxicity, vasculitis damage index, serious adverse events and adverse events of interest, NHS resource use, relevant out of pocket cost and lost productivity. The total trial duration is 66 months with a 30-month recruitment period and a maximum follow up of 24 months. Statistical analysis: All vasculitis subgroups will be combined for the primary analysis; secondary analyses will test disease subgroups. The trial has 90% power (two-sided 5% significance level) when placebo has a mean TTF of 3.6 months and an experimental treatment has a mean TTF of 6 months. Treatment effects will be analysed for each diagnostic subgroup with a mixed-effects Cox regression model; Bayesian hierarchical analyses will be used for subgroups with a sample size < 30 where a prior can reasonably be determined. Health economic analysis will be used to compare each biologic to placebo. Summary: This study addresses patients with refractory vasculitis who have the highest unmet need. It will compare three biologics with different targets to placebo in a double-blind trial across the spectrum of rare vasculitis syndromes. The trial involves UK vasculitis specialists, is supported by the UKIVAS organization, the Specialist Rheumatology networks, and patients. It is designed to be a pragmatic trial in rare disease groups aiming to generate good quality evidence to improve patient outcomes and to support policymaking.

Lay abstract: The vasculitis diseases occur when the body’s immune system attacks blood vessels, causing injury to the vessel and the part of the body it supplies with blood. Vasculitis is rare, there are a number of different types, and they affect both adults and children. We treat vasculitis with steroids and drugs aiming to damp down the activity of the immune system, but they often cause side effects. Some patients do not improve with this treatment, or cannot tolerate it and their vasculitis worsens (refractory vasculitis). Such patients are at high risk of health complications from the disease and its therapy and are in need of newer treatments with fewer side effects. Biologics are newer expensive drugs manufactured from biological sources. They are designed to precisely target the immune system and have fewer side effects. Although biologics have been used for some years to treat vasculitis, for many types of vasculitis we do not have good data to guide the correct choice of biologic, and when to use it. Two biologics have been fully tested and are now licensed for the more common forms of vasculitis. We want to establish whether biologics are effective and represent value for money for patients with refractory vasculitis. BIOVAS will look at three different biologics, infliximab (INF), tocilizumab (TCZ) and rituximab (RTX), chosen for scientific reasons and because there is already experience of their use in vasculitis. We will recruit 140 adults and children with refractory vasculitis and compare each drug to a placebo (dummy) treatment. Patients will have the following types of vasculitis: giant cell arteritis, Takayasu’s arteritis, polyarteritis nodosa, cerebral vasculitis, Cogan’s syndrome, relapsing polychondritis, IgA vasculitis, non-infective cryoglobulinaemic vasculitis. Patients will not be able to take part if they have recently received a biologic drug, have a serious infection, or are pregnant. Treatments will be decided by a process called randomisation (like “flipping a coin”). Patients will be assigned to a treatment sequence (e.g. one sequence may be TCZ, then INF, then placebo, then RTX). They will start on the first allocated treatment and stay on it as long as it is helping them; if the treatment does not work, or stops working, they will move to the next treatment in the sequence. Neither the doctor nor the patient will know which treatment they are on unless there is an emergency. All treatments are given through a drip into a vein in the patient’s arm. Patients will be seen in clinic at the start of the trial and every four months to see how they are doing. These visits will check whether the treatment is working or not. Patients will be asked to complete questionnaires about how they feel the disease is affecting their lives, as well as recording side effects. The study will estimate the money spent on the patient by the NHS, costs the patient experience due to the disease and whether the disease is affecting their job or education. We hope to show whether biologics work or not, which one works best, what affect they have on patient’s health and quality of life, and whether the drug costs can be justified. The BIOVAS study team includes experts in vasculitis and patient representatives. This will help patients in the future to receive the best possible treatment for their conditions.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM