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

NCT05168475 | Terminated Phase 2 Results DMC

• 1 other identifier: BIOVAS
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 5

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)

Conditions

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

Keywords

vasculitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP

  120 days

• Patients Achieving Response at Any 120 Day Timepoint

  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 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)

  120 days, 240 days, 360 days, 480 days, 600 days, 720 days

• Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs)

  up to 720 days

Study Arms (4)

Rituximab

ACTIVE COMPARATOR

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; Biological: Tocilizumab

Infliximab

ACTIVE COMPARATOR

Infliximab 5mg/kg IV on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) then every 56 days (+/-14d) thereafter.

Biological: Rituximab; Biological: Tocilizumab

Tocilizumab

ACTIVE COMPARATOR

Tocilizumab 8mg/kg IV (maximum 800mg) every 30 days (+/- 7d); 10 mg/kg (maximum 800 mg) for children \< 30 kg.

Biological: Rituximab; Biological: Infliximab

Placebo

PLACEBO COMPARATOR

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; Biological: Infliximab; Biological: Tocilizumab

Interventions

Rituximab BIOLOGICAL

Hospital stock of rituximab used as intervention; biosimilars are allowed

Infliximab; Placebo; Tocilizumab

Infliximab BIOLOGICAL

Hospital stock of infliximab is used in the trial; biosimilars are allowed

Placebo; Rituximab; Tocilizumab

Tocilizumab BIOLOGICAL

Hospital-supplied stock.

Infliximab; Placebo; Rituximab

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead

Study Sites (5)

Cambridge University Hospitals NHS Foundation Trust

Cambridge, United Kingdom

Location

Glasgow Royal Infirmary

Glasgow, United Kingdom

Location

Great Ormond Street Hospital NHS Foundation Trust

London, United Kingdom

Location

Guy's and St Thomas

London, United Kingdom

Location

East Kent Hospitals

Margate, United Kingdom

Location

MeSH Terms

Conditions

Giant Cell Arteritis; Takayasu Arteritis; Cogan Syndrome; Polychondritis, Relapsing; Cryoglobulinemia, Familial Mixed; IgA Vasculitis; Polyarteritis Nodosa; Vasculitis

Interventions

Rituximab; Infliximab; tocilizumab

Condition Hierarchy (Ancestors)

Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Aortic Arch Syndromes; Aortic Diseases; Vestibulocochlear Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Cartilage Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemostatic Disorders; Hemorrhagic Disorders; Immune Complex Diseases; Hypersensitivity; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms; Systemic Vasculitis

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The recruitment period was planned to be 29 months, however study activities were halted after 20 months due to funding being withdrawn. 18 participants were randomised rather than the intended sample size of 140. Due to the small number of participants recruited the analyses are mainly descriptive.

Results Point of Contact

• Title: Professor David Jayne
• Organization: Cambridge University Hospitals NHS Foundation Trust

dj106@cam.ac.uk

01223 336816

Study Officials

• David Jayne

  Cambridge University Hospitals NHS Foundation Trust/University of Cambridge

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind to patient and trial team. Pharmacy and central coordinator unblinded to minimise risk
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Honorary Consultant Physician

Model Details: Modified-crossover; participants are randomised to a fixed sequence of 4 trial IMPs. Each sequence will consist of 3 active IMP treatments and a placebo. The order of the IMPs in each sequence will be randomly allocated (e.g. RTX-INF-TCZ-PBO or INF-PBO-RTX-TCZ) from a list of 24 permutations. Further, the placebo in each sequence will be randomly allocated to mirror the drug administration schedule of 1 of the active IMPs in order to maintain the blind resulting in 72 different possible permutations

Study Record Dates

• First Submitted: December 9, 2021
• First Posted: December 23, 2021
• Study Start: July 14, 2021
• Primary Completion: November 29, 2023
• Study Completion: November 29, 2023
• Last Updated: June 17, 2025
• Results First Posted: June 17, 2025

Record last verified: 2025-05

Locations

GB (5)