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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 22
- 试验地点
- 5
- 主要终点
- Treatment Failure
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Double-blind to patient and trial team. Pharmacy and central coordinator unblinded to minimise risk
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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).
干预措施: Infliximab (Biological)
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).
干预措施: Tocilizumab (Biological)
Infliximab
Infliximab 5mg/kg IV on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) then every 56 days (+/-14d) thereafter.
干预措施: Rituximab (Biological)
Infliximab
Infliximab 5mg/kg IV on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) then every 56 days (+/-14d) thereafter.
干预措施: Tocilizumab (Biological)
Tocilizumab
Tocilizumab 8mg/kg IV (maximum 800mg) every 30 days (+/- 7d); 10 mg/kg (maximum 800 mg) for children < 30 kg.
干预措施: Rituximab (Biological)
Tocilizumab
Tocilizumab 8mg/kg IV (maximum 800mg) every 30 days (+/- 7d); 10 mg/kg (maximum 800 mg) for children < 30 kg.
干预措施: Infliximab (Biological)
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.
干预措施: Rituximab (Biological)
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.
干预措施: Infliximab (Biological)
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.
干预措施: Tocilizumab (Biological)
结局指标
主要结局
Treatment Failure
时间窗: up to 720 days
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.
次要结局
- 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)
研究者
David Jayne
Honorary Consultant Physician
Cambridge University Hospitals NHS Foundation Trust