Biologics in Refractory Vasculitis: A Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis

Inclusion Criteria:

1. Aged at least 5 years

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

3. Diagnosis of NAAV (Appendix 4)

4. Refractory disease defined by:

• Active disease, BVASv3-BIOVAS/ PVAS with ≥ 1 severe (new/worse) or ≥ 3non-severe (new/worse) items despite 12 weeks of conventional therapy prior toscreening visit OR

• Inability to reduce prednisolone below 15mg/day or (0.2mg/kg/day in case ofchildren) without relapse in the 12 weeks prior to screening visit

Exclusion Criteria:

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 of screening visit

3. Use of intravenous immunoglobulins within 30 days, or cyclophosphamide or lymphocytedepleting 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 IMPsduring the trial period

5. Have an active systemic bacterial, viral or fungal infection, or tuberculosis

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

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

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

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

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, neutrophilcount of < 2 x 109 cells/l

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

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

14. Demyelinating disorders

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

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 30days 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