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

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

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)

Study Overview

• Status: Terminated
• Conditions: Giant Cell Arteritis; Polyarteritis Nodosa; Takayasu Arteritis; Cryoglobulinemic Vasculitis; IgA Vasculitis; Cogan Syndrome; Relapsing Polychondritis; Cutaneous Polyarteritis Nodosa; Primary Angiitis of Central Nervous System
• Intervention / Treatment: Biological: Infliximab; Biological: Tocilizumab; Biological: Rituximab

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 Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NHS Foundation Trust
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • London, United Kingdom
    • Great Ormond Street Hospital NHS Foundation Trust
  • London, United Kingdom
    • Guy's and St Thomas
  • Margate, United Kingdom
    • East Kent Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (Appendix 4)

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:

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 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 during 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 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;see 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. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Infliximab; Hospital stock of infliximab is used in the trial; biosimilars are allowed; Biological: Tocilizumab; Hospital-supplied stock.; Biological: Rituximab; Hospital stock of rituximab used as intervention; biosimilars are allowed
Active Comparator: Rituximab; Rituximab 1g IV on Days 1, 15 (+/-3d), 180 (+/-14d), 360 (+/-14d) and 540 (+/-14d). (Children, 750mg/m2/dose, maximum 1 g per dose).	Biological: Infliximab; Hospital stock of infliximab is used in the trial; biosimilars are allowed; Biological: Tocilizumab; Hospital-supplied stock.
Active Comparator: Infliximab; Infliximab 5mg/kg IV on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) then every 56 days (+/-14d) thereafter.	Biological: Tocilizumab; Hospital-supplied stock.; Biological: Rituximab; Hospital stock of rituximab used as intervention; biosimilars are allowed
Active Comparator: Tocilizumab; Tocilizumab 8mg/kg IV (maximum 800mg) every 30 days (+/- 7d); 10 mg/kg (maximum 800 mg) for children < 30 kg.	Biological: Infliximab; Hospital stock of infliximab is used in the trial; biosimilars are allowed; Biological: Rituximab; Hospital stock of rituximab used as intervention; biosimilars are allowed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Failure	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 trial (BVASv3-BIOVAS) or paediatric vasculitis activity score (PVAS) within 120 days from the time of IMP commencement; or failure to achieve clinical response (see definitions below) by 120 days from the time of IMP commencement. In such cases, TTF will be recorded as zero. We report this as number of events that occurred. As arms reached the number of events to define a median, we are reporting it as number of events.	up to 720 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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. The response status is defined by a BVAS v3-BIOVAS/ PVAS of ≤ one 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	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 Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment	VDI/PVDI scores are collected from 11 different disease categories with each positive item scoring one mark. VDI/PVDI scores can either increase or stay the same at each measurement. All damage scores are carried forward to the next assessment. The minimum score is zero and the maximum score is 63. A low score indicates less damage and therefore a better outcome. A higher score indicates more damage and a worse outcome. Due to the study design, participants were kept on each intervention until treatment failure and then moved to the next in their allocated sequence. Secondary outcome data were collected from the start of the first treatment without restarting collection at each crossover. Therefore, results are presented by treatment sequence. The number of participants analysed includes all participants who received the given intervention at any time during the study.	VDI/PVDI scores were collected every 120 days at each scheduled visit in the trial until the last assessment at day 720 at the end of trial. 120 days, 240 days, 360 days, 480 days, 600 days and 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 The Physician's global assessment (PGA) is a visual analogue scale from 0-10, where 0 is no disease activity (better outcome) and 10 is maximum disease activity (worse outcome). PGA scores are collected every 120 days at each scheduled visit for each participant (unless a visit is unscheduled which could occur at any time in between the time points). Due to the study design, participants were kept on each intervention until treatment failure and then moved to the next in their allocated sequence. Secondary outcome data were collected from the start of the first treatment without restarting collection at each crossover. Therefore, results are presented by treatment sequence. The number of participants analysed includes all participants who received the given intervention at any time during the study.	120 days, 240 days, 360 days, 480 days, 600 days, 720 days
Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs)	Serious adverse events (SAEs) and adverse events of special interest (AESI) (where infection is considered an AESI)	up to 720 days

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: David Jayne, Cambridge University Hospitals NHS Foundation Trust/University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2021
• Primary Completion (Actual): November 29, 2023
• Study Completion (Actual): November 29, 2023

Study Registration Dates

• First Submitted: December 9, 2021
• First Submitted That Met QC Criteria: December 9, 2021
• First Posted (Actual): December 23, 2021

Study Record Updates

• Last Update Posted (Actual): June 17, 2025
• Last Update Submitted That Met QC Criteria: May 29, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: vasculitis
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Pathologic Processes; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Hemorrhage; Skin Manifestations; Eye Diseases; Hypersensitivity; Hematologic Diseases; Autoimmune Diseases of the Nervous System; Skin Diseases; Blood Coagulation Disorders; Skin Diseases, Vascular; Hemostatic Disorders; Hemorrhagic Disorders; Cranial Nerve Diseases; Aortic Diseases; Purpura; Vestibulocochlear Nerve Diseases; Vasculitis, Central Nervous System; Cartilage Diseases; Immune Complex Diseases; Systemic Vasculitis; Polymyalgia Rheumatica; Polychondritis, Relapsing; Giant Cell Arteritis; Vasculitis; Arteritis; Takayasu Arteritis; Aortic Arch Syndromes; Polyarteritis Nodosa; IgA Vasculitis; Cogan Syndrome; Antineoplastic Agents, Immunological; Tumor Necrosis Factor Inhibitors; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Inflammatory Agents; Gastrointestinal Agents; Antirheumatic Agents; Dermatologic Agents; Rituximab; Infliximab
• Other Study ID Numbers: BIOVAS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No