Patients with relapsing or refractory non-ANCA-associated vasculitis (NAAV). Specific diseases to be included in this trial are: giant cell arteritis (GCA), Takayasu's arteritis (TA), polyarteritis nodosa (PAN), relapsing polychondritis, IgA vasculitis (of adults and children), cryoglobulinaemia, Cogan's syndrome and primary central nervous system (CNS) vasculitis Circulatory System 1. Other giant cell arteritis 2. Polyarteritis nodosa and related conditions 3. Relapsing polychondritis 4. Cryo
Conditions
Interventions
The treatments to be studied are rituximab, tocilizumab and infliximab. Eligible patients will be randomized to a sequence of the three biologics plus a placebo to one of the biologics in a blinded m
however, 36 sequences enable unblinding. Therefore there are 24 possible permutations that patients may be randomized to. An example is: rituximab-infliximab-tociluzumab placebo-tocilizumab.
Patient
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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: 4.1. Active disease, BVAS v3/ PVAS with = 1 severe (new/worse) or = 3 non-severe (new/worse) items despite 12 weeks of conventional therapy prior to screening visit OR 4.2. Inability to reduce prednisolone below 15 mg/day or (0.2 mg/kg/day in case of children) without relapse in the 12 weeks prior to screening visit
Exclusion criteria
Exclusion criteria: 1. Previous treatment failure/contraindication to =2 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 lymphocyte depleting biologic (e.g. rituximab) within 6 months of screening visit 4. Have an active systemic bacterial, viral or fungal infection, or tuberculosis 5. Hepatitis B (HB) core antibody (Ab) or HB surface antigen-positive or hepatitis C antibody positive or human immunodeficiency virus (HIV) antibody test positive 6. 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 7. Pregnant or breastfeeding (Section 11.9) 8. Severe disease, which in the opinion of the physician prevents randomization to placebo 9. Recent or upcoming major surgery within 45 days of screening visit 10. Leukocyte count 3 times the upper limit of normal 12. Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication within 90 days of screening visit 13. Demyelinating disorders 14. 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 15. Administration of live or live-attenuated vaccines within 45 days of screening 16. Have received an investigational medicinal product (IMP) within 5 half-lives or 30 days prior to screening 17. Diagnosis of adenosine deaminase type 2 (DADA2) 18. Hypersensitivity to the active IMP substance or to any of the formulation excipients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to treatment failure (TTF): the time from the start of IMP treatment, to treatment failure. Primary treatment failure is: 1. Progressive disease (defined by appearance of =1 new/worse severe or =3 new/worse non-severe items) on Birmingham vasculitis activity score (BVAS) v3 or paediatric vasculitis activity score (PVAS) within 120 days from the time of IMP commencement OR 2. Failure to achieve clinical response by 120 days from the time of IMP commencement Clinical response is defined as: 1. Absence of new/worse BVAS V3 (adults)/PVAS (children) items assessed at each 120 evaluation time point after commencing IMP AND 2. Prednisolone =10 mg/day or =0.2 mg/kg for children (whichever is lower), unless the baseline dose is =10 mg/day or =0.2 mg/kg for children (whichever is lower), in which case it should not be more than the baseline dose* *baseline dose is the dose of oral prednisolone, mg/day, or equivalent oral steroid, averaged over the 7 days prior to the start of each new IMP. Secondary treatment failure is relapse having achieved a clinical response by 120 days of commencing IMP. Relapse is defined as: 1. Appearance of = 1 severe (new/worse) or = 3 non-severe (new/worse) BVAS v3/PVAS items from the time of BVAS response (as defined above) assessed at the 120 day evaluation time points OR 2. The need to increase the dose of prednisolone to > 20 mg/day to treat vasculitis OR 3. The need to increase the dose of an immunomodulator or immune-suppressive therapy in order to treat vasculitis | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Treatment effects of each of the IMPs compared to placebo and each IMP against other IMPs in two NAAV sub-groups: large vessel vasculitis (GCA/TA) and all other NAAV subgroups enrolled in the trial; measured by Bayesian priors meeting followed by statistical analysis of final dataset 2. Proportion of participants achieving response at 120 days evaluation after the start of each IMP, as measured by the response definitions provided in primary outcome measure 3. Proportion of participants achieving response at every 120-day evaluation timepoint defined by a BVAS v3/ PVAS of = one non-severe (no new/worse) item, prednisolone dose = 50% of the dose at the start of the IMP treatment and = 10 mg/day (0.2 mg/kg/day for children, whichever is lower) and an ESR < 30 mm/h or CRP <10 mg/l assessed by BVAS v3/PVAS, review of participant daily steroid diary and standard of care clinical blood test review of ESR and CRP results at each 120-day trial visit 4. Disease-related damage measured by VDI/PVDI from start to end of an IMP treatment, recorded at each 120-day trial visit and at any relapse unscheduled visit 5. Disease activity measured using Physician’s global assessment (PGA) (Likert scale 0-10) at every 120-day evaluation timepoint from the time of IMP commencement 6. Serious adverse events/adverse events of special interests; SAEs/AESI review throughout the trial 7. Patient-reported health and wellbeing measured using EQ-5D-5L or Child Health Utility (CHU9D) assessments at every 120-day evaluation timepoint 8. NHS resource use and out of pocket costs and lost productivity, measured using health resource use questionnaire for adults and children/parent/guardian, recorded at each 120-day trial visit | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactKim Maynard
Outcome results
None listed