Clinical trial NCT05168475: Biologics in Refractory Vasculitis: A Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
First posted: 2021-12-23
Enrollment: 22
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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
Primary purpose: TREATMENT

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)

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.

Eligibility 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 (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

Primary outcomes:
measure: Treatment Failure
timeFrame: up to 720 days
Secondary outcomes:
measure: Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP
timeFrame: 120 days
measure: Patients Achieving Response at Any 120 Day Timepoint
timeFrame: up to 720 days
measure: Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment
timeFrame: 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
measure: Physician's Global Assessment (PGA) (Likert Scale 0-10)
timeFrame: 120 days, 240 days, 360 days, 480 days, 600 days, 720 days
measure: Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs)
timeFrame: up to 720 days
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: London
country: United Kingdom
facility: Great Ormond Street Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas
city: Margate
country: United Kingdom
facility: East Kent Hospitals
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust/University of Cambridge
name: David Jayne
role: PRINCIPAL_INVESTIGATOR
References: