Biologics in refractory vasculitis

Research summary

Glucocorticoids remain the standard therapy for remission induction in non-ANCA associated vasculitis (NAAV) and are used with or without immunosuppressive agents depending on the syndrome and severity. Glucocorticoids at high doses control systemic inflammation and reduce acute injury but may not induce long-term treatment free remission and carry a heavy burden of almost universal toxicity. Vasculitides are characterised by frequent relapses, which further contribute to disease-related damage and drug-related toxicity.

Steroid use is associated with the risk of diabetes, hypertension, thrombosis, gastro-intestinal haemorrhage, psychosis, insomnia, skin fragility, changed appearance, alopecia, osteoporosis, infections and obesity. The elderly are particularly vulnerable to an increased risk of fragility fractures and cataracts that have major impacts on their mobility and quality of life. Analyses of European Vasculitis Study group (EUVAS) clinical trials have shown that the majority of deaths within the first 12 months are treatment-related adverse events, such as infections (48%). In a French study of ANCA associated vasculitis (AAV) participants around 90% of serious infections occurred in relation to glucocorticoids and reduced doses or alternate day dosing regimens were associated with reduced infections. Thus, there is a clear and important need to reduce the use of glucocorticoids in NAAV.

BIOVAS is a multi-centre, pragmatic, randomised double blind, placebo-controlled, modified-crossover phase 2B trial of infliximab, rituximab and tocilizumab for refractory NAAV in adults and children. The trial will test the hypothesis that biologics are superior to placebo in the control of refractory NAAV. Each of the three trial biologics (infliximab, rituximab and tocilizumab) will be compared to placebo in a sequential modified crossover, placebo-controlled design.

Main inclusion criteria

To be included in the trial the participant must:

  1. Aged at least 5 years

  2. Have given, or their parent/legal guardian aged ≥ 16 years old has given, written informed consent

  3. Diagnosis of NAAV

  4. Refractory disease defined by:

    • Active disease, BVAS v3-BIOVAS/ PVAS with ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) items despite 12 weeks of conventional therapy OR

    • Inability to reduce prednisolone below 15mg/day or (0.3mg/kg/day in case of children) without relapse in the 12 weeks prior to screening visit

Main exclusion criteria

Participants are excluded from the trial if any of the following criteria apply:

  1. Previous treatment failure/contraindication to ≥ 2 active trial IMPs

  2. Increase in the dose or frequency of background immunosuppressive (e.g. methotrexate) or anti-cytokine therapy within 30 days prior to screening visit

  3. Use of plasma exchange or intravenous immunoglobulins within the 30 days, or cyclophosphamide or lymphocyte depleting biologic (e.g. rituximab) within 6 months of screening visit

  4. Concomitant use of any biologic and/or anti-TNF agent other than the trial IMPs for the duration of the trial.

  5. Have an active systemic bacterial, viral or fungal infection, or active/latent tuberculosis assessed/documented as per local clinical practice; this includes COVID19 testing if warranted and as per local routine practice.

  6. Hepatitis B (HB) core antibody (Ab) or HB surface antigen positive or hepatitis C antibody positive or human immunodeficiency virus (HIV) antibody test positive

  7. History of malignancy within five years prior to screening visit or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure

  8. Pregnant or breastfeeding, or inability/unwillingness to use a highly effective method of contraceptive if a woman of childbearing potential (WOCBP; Section 11.9)

  9. Severe disease, which in the opinion of the physician prevents randomisation to placebo

  10. Recent or upcoming major surgery within 45 days of screening visit

  11. Leukocyte count < 3.5 x 109 cells/l, platelet count < 100 x 109 cells/l, neutrophil count of < 2 x 109 cells/l

  12. 12. ALT or ALP > 3 times the upper limit of normal

  13. Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication within 90 days of screening visit

  14. Demyelinating disorders

  15. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the participant at unacceptable risk because of trial participation

  16. Administration of live or live attenuated vaccines within 45 days of screening

  17. Have received an investigational medicinal product (IMP) within 5 half-lives or 30 days prior to screening

  18. Diagnosis of adenosine deaminase type 2 (DADA2)

  19. Hypersensitivity to the active IMP substance or to any of the formulation excipients (unless IMP excluded for a particular patient pre-randomisation)

Chief investigator

Prof David Jayne

Contact details

Senior Clinical Trials Coordinator: Dr Maria King

Telephone: 01223 596441 | Email: [email protected]