Biologics in Refractory Vasculitis

Study Overview
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Brief Summary
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Vasculitis occur when the body's immune system, rather than protecting the body, attacks blood vessels, causing injury to the vessel and the part of the body it supplies with blood. Vasculitis is rare, and there are a number of different types, which can 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; this is known as refractory vasculitis. Patients with refractory vasculitis are at high risk of health complications from the disease and its therapy and are in need of newer more effective treatments with fewer side effects. Biologics are drugs which are designed to precisely target parts of the immune system and may have fewer side effects. Biologics have been used for several years to treat vasculitis, particularly anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis or AAV. However, for many of the rarer types of vasculitis, and especially those vasculitis disease types that are not ANCA-associated, there is little information to support use of biologic therapies as effective treatments. The purpose of this trial is to find out whether biologics are effective and represent value for money for participants with refractory vasculitis. The trial will include patients with Non-ANCA-associated vasculitis (NAAV)

Detailed Description
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The trial is a multi-centre, randomised, double-blind, placebo-controlled, modified-crossover design which will investigate three biologics, Infliximab, Rituximab, Tocilizumab, and placebos to each, in the treatment of refractory non-ANCA-associated Vasculitis (NAAV) in adults and children. Eligible patients are randomised to a sequence of up to 4 interventions (comprising 3 biologics and 1 placebo to one of the three biologics being studied). Patients remain on first intervention in their randomised sequence for up to 2 years, or until they are deemed to fail treatment or experience a severe disease relapse, at which point they will be switched to the next intervention in their randomised sequence. When a patient switches to the next intervention in their randomised sequence, they will again remain on treatment either until the end of treatment period or until they fail treatment or experience a severe disease relapse. Patients remain on the treatment period for a maximum of 2 years, or until they have failed/experienced severe relapses on every treatment in their randomised sequence, whichever is sooner. Patients will be assessed for disease activity and relapse every 120 days up to D720.

Official Title
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Biologics in Refractory Vasculitis (BIOVAS): A Pragmatic, Randomised, Double-blind, Placebo-controlled, Modified-crossover Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis in Adults and Children

Conditions
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Giant Cell Arteritis, Takayasu Arteritis, Cogan Syndrome, Relapsing Polychondritis, Cryoglobulinemic Vasculitis, IgA Vasculitis, Polyarteritis Nodosa, Cutaneous Polyarteritis Nodosa, Primary Angiitis of Central Nervous System

Intervention / Treatment
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* Biological: Rituximab
* Biological: Infliximab
* Biological: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged at least 5 years Have given, or their parent/ legal guardian aged ≥ 16 years old has given, written informed consent Diagnosis of NAAV (Appendix 4) Refractory disease defined by: Active disease, BVASv3-BIOVAS/ PVAS with ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) items despite 12 weeks of conventional therapy prior to screening visit OR Inability to reduce prednisolone below 15mg/day or (0.2mg/kg/day in case of children) without relapse in the 12 weeks prior to screening visit Exclusion Criteria: Previous treatment failure/contraindication to ≥ 2 active trial IMPs Increase in the dose or frequency of background immunosuppressive (e.g. methotrexate) or anti-cytokine therapy within 30 days of screening visit Use of intravenous immunoglobulins within 30 days, or cyclophosphamide or lymphocyte depleting biologic (e.g. rituximab) within 6 months of screening visit Concomitant use of any biologic and/or anti-TNF agent other than the trial IMPs during the trial period Have an active systemic bacterial, viral or fungal infection, or tuberculosis Hepatitis B (HB) core antibody (Ab) or HB surface antigen positive or hepatitis C antibody positive or human immunodeficiency virus (HIV) antibody test positive 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 Pregnant or breastfeeding, or inability/unwillingness to use a highly effective method of contraceptive if a woman of childbearing potential (WOCBP;see section 11.9) Severe disease, which in the opinion of the physician prevents randomisation to placebo Recent or upcoming major surgery within 45 days of screening visit Leukocyte count < 3.5 x 109 cells/l, platelet count < 100 x 109 cells/l, neutrophil count of < 2 x 109 cells/l ALT or ALP > 3 times the upper limit of normal Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication within 90 days of screening visit Demyelinating disorders 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 Administration of live or live attenuated vaccines within 45 days of screening Have received an investigational medicinal product (IMP) within 5 half-lives or 30 days prior to screening Diagnosis of adenosine deaminase type 2 (DADA2) Hypersensitivity to the active IMP substance or to any of the formulation excipients

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Modified-crossover; patients are randomised to a sequence of up to 4 interventions (3x active plus 1x placebo); there are a total of 24 possible sequences a patient can be randomised to.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab<br> | Biological: Infliximab<br>* Hospital stock of infliximab is used in the trial; biosimilars are allowed<br>Biological: Tocilizumab<br>* Hospital-supplied stock.<br>|
| Active Comparator: Infliximab<br> | Biological: Rituximab<br>* Hospital stock of rituximab used as intervention; biosimilars are allowed<br>Biological: Tocilizumab<br>* Hospital-supplied stock.<br>|
| Active Comparator: Tocilizumab<br> | Biological: Rituximab<br>* Hospital stock of rituximab used as intervention; biosimilars are allowed<br>Biological: Infliximab<br>* Hospital stock of infliximab is used in the trial; biosimilars are allowed<br>|
| Placebo Comparator: Placebo<br>Placebo may be to one of the active biologics (ie placebo to Rituximab, Placebo to Infliximab, placebo to Tocilizumab). Only 1 placebo is in a randomised sequence of interventions. | Biological: Rituximab<br>* Hospital stock of rituximab used as intervention; biosimilars are allowed<br>Biological: Infliximab<br>* Hospital stock of infliximab is used in the trial; biosimilars are allowed<br>Biological: Tocilizumab<br>* Hospital-supplied stock.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TTF; primary treatment failure) | TTF for each IMP is the time from the start of IMP treatment, to treatment failure or the end of trial participation (censored). Primary treatment failure is progressive disease (defined by appearance of ≥1 new/worse severe or ≥3 new/worse non-severe items) on Birmingham vasculitis activity score (BVAS) v3 modified for BIOVAS (BVAS v3-BIOVAS) or paediatric vasculitis activity score (PVAS) within 120 days from the time of IMP commencement; or failure to achieve clinical response by 120 days from the time of IMP commencement | 120 days from commencement of treatment | 
| Time to treatment failure (TTF; secondary treatment failure) | TTF is time from start of IMP treatment, to treatment failure. Secondary treatment failure isis defined as having achieved response (definition below) by 120 days from the time of IMP commencement, and subsequently relapse after 120 days from IMP commencement | up to 720 days | 
| Treatment failure due to adverse reaction | Where a patient experiences an adverse reaction to a treatment which precludes the patient from receiving further doses of that intervention, this is also considered treatment failure | up to 720 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bayesian analysis | Bayesian hierarchical analysis to assess treatment effects of each of the IMPs compared to placebo and each IMP against other IMPs in 2 NAAV sub-groups: large vessel vasculitis (GCA/TA) and all other NAAV subgroups enrolled in the trial | 720 days | 
| Patients achieving response at the 120 day timepoint following commencement of IMP | Proportion of participants achieving response at the 120 day evaluation time point after the start of each IMP. | 120 days | 
| Patients achieving response at any 120 day timepoint | Proportion of participants achieving response at every 120 day evaluation time point defined by a BVAS v3-BIOVAS/ PVAS of ≤ 1 non-severe (no new/worse) item, prednisolone dose ≤ 50% of the dose at the start of the IMP treatment and ≤ 10mg/day (0.2 mg/kg/day for children, whichever is lower) and an ESR < 30mm/hr or CRP <10 mg/L | up to 720 days | 
| Increase in disease-related damage | Increase in disease related damage measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) from start to end of an IMP treatment | up to 720 days | 
| Physician's global assessment (PGA) (Likert scale 0-10) | Physician's global assessment at every 120 day evaluation time point from the time of IMP commencement | 120 days | 
| Serious adverse events/adverse events of special interests (SAEs/AESIs) | SAEs and AESI (where infection is considered an AESI) | up to 720 days | 
| Patient-reported outcomes | EQ-5D-5L or Child Health Utility (CHU9D) assessments at every 120 day evaluation time point | 120 days | 
| National Health Service (NHS) resource use and out of pocket costs and lost productivity | Assessed every 120 days by questionnaire and at end of trial by health economics analysis | up to 720 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vasculitis