BIOVAS: Biologics in Refractory Vasculitis

Sponsor

Cambridge University Hospitals NHS Foundation Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT05168475

Collaborator

(none)

140

Enrollment

Locations

Arms

52.6

Anticipated Duration (Months)

46.7

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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)

Condition or Disease	Intervention/Treatment	Phase
Giant Cell Arteritis Takayasu Arteritis Cogan Syndrome Relapsing Polychondritis Cryoglobulinemic Vasculitis IgA Vasculitis Polyarteritis Nodosa Cutaneous Polyarteritis Nodosa Primary Angiitis of Central Nervous System	Biological: Rituximab Biological: Infliximab Biological: Tocilizumab	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention 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.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 (Participant, Investigator, Outcomes Assessor)

Masking Description:

Double-blind to patient and trial team. Pharmacy and central coordinator unblinded to minimise risk

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 14, 2021

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rituximab	Biological: Infliximab Hospital stock of infliximab is used in the trial; biosimilars are allowed Biological: Tocilizumab Hospital-supplied stock.
Active Comparator: Infliximab	Biological: Rituximab Hospital stock of rituximab used as intervention; biosimilars are allowed Biological: Tocilizumab Hospital-supplied stock.
Active Comparator: Tocilizumab	Biological: Rituximab Hospital stock of rituximab used as intervention; biosimilars are allowed Biological: Infliximab Hospital stock of infliximab is used in the trial; biosimilars are allowed
Placebo Comparator: Placebo 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 Hospital stock of rituximab used as intervention; biosimilars are allowed Biological: Infliximab Hospital stock of infliximab is used in the trial; biosimilars are allowed Biological: Tocilizumab Hospital-supplied stock.

Outcome Measures

Primary Outcome Measures

Time to treatment failure (TTF; primary treatment failure) [120 days from commencement of treatment]
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
Time to treatment failure (TTF; secondary treatment failure) [up to 720 days]
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
Treatment failure due to adverse reaction [up to 720 days]
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

Secondary Outcome Measures

Bayesian analysis [720 days]
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
Patients achieving response at the 120 day timepoint following commencement of IMP [120 days]
Proportion of participants achieving response at the 120 day evaluation time point after the start of each IMP.
Patients achieving response at any 120 day timepoint [up to 720 days]
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
Increase in disease-related damage [up to 720 days]
Increase in disease related damage measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) from start to end of an IMP treatment
Physician's global assessment (PGA) (Likert scale 0-10) [120 days]
Physician's global assessment at every 120 day evaluation time point from the time of IMP commencement
Serious adverse events/adverse events of special interests (SAEs/AESIs) [up to 720 days]
SAEs and AESI (where infection is considered an AESI)
Patient-reported outcomes [120 days]
EQ-5D-5L or Child Health Utility (CHU9D) assessments at every 120 day evaluation time point
National Health Service (NHS) resource use and out of pocket costs and lost productivity [up to 720 days]
Assessed every 120 days by questionnaire and at end of trial by health economics analysis

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Cambridge University Hospitals NHS Foundation Trust	Cambridge	United Kingdom
2	Glasgow Royal Infirmary	Glasgow	United Kingdom
3	Great Ormond Street Hospital NHS Foundation Trust	London	United Kingdom