Cogan Syndrome, Cryoglobulinemic Vasculitis, Cutaneous Polyarteritis Nodosa, Giant Cell Arteritis, IgA Vasculitis, Polyarteritis Nodosa, Primary Angiitis of Central Nervous System, Relapsing Polychondritis, Takayasu Arteritis
Conditions
Keywords
vasculitis
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.
Interventions
BIOLOGICALRituximab
Hospital stock of rituximab used as intervention; biosimilars are allowed
BIOLOGICALInfliximab
Hospital stock of infliximab is used in the trial; biosimilars are allowed
BIOLOGICALTocilizumab
Hospital-supplied stock.
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Double-blind to patient and trial team. Pharmacy and central coordinator unblinded to minimise risk
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
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. 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 |
| 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 | 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. |
| Physician's Global Assessment (PGA) (Likert Scale 0-10) | 120 days, 240 days, 360 days, 480 days, 600 days, 720 days | 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. |
| Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | up to 720 days | Serious adverse events (SAEs) and adverse events of special interest (AESI) (where infection is considered an AESI) |
Countries
United Kingdom
Participant flow
Pre-assignment details
4 participants were excluded as they did not meet the inclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| 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).
Infliximab: Hospital stock of infliximab is used in the trial; biosimilars are allowed
Tocilizumab: Hospital-supplied stock. | 7 |
| Infliximab Infliximab 5mg/kg IV on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) then every 56 days (+/-14d) thereafter.
Rituximab: Hospital stock of rituximab used as intervention; biosimilars are allowed
Tocilizumab: Hospital-supplied stock. | 7 |
| Tocilizumab Tocilizumab 8mg/kg IV (maximum 800mg) every 30 days (+/- 7d); 10 mg/kg (maximum 800 mg) for children \< 30 kg.
Rituximab: Hospital stock of rituximab used as intervention; biosimilars are allowed
Infliximab: Hospital stock of infliximab is used in the trial; biosimilars are allowed | 3 |
| 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.
Rituximab: Hospital stock of rituximab used as intervention; biosimilars are allowed
Infliximab: Hospital stock of infliximab is used in the trial; biosimilars are allowed
Tocilizumab: Hospital-supplied stock. | 1 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1 | IMP shortage | 2 |
| Period 1 | Not randomised | 2 |
| Period 1 | Protocol Violation | 1 |
| Period 2 | IMP shortage | 1 |
Baseline characteristics
| Characteristic | Rituximab | Infliximab | Tocilizumab | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 2 Participants | 1 Participants | 12 Participants |
| Age, Continuous | 46.57 years STANDARD_DEVIATION 25.55 | 48.57 years STANDARD_DEVIATION 14.41 | 54.67 years STANDARD_DEVIATION 21.2 | 58 years STANDARD_DEVIATION 0 | 49.33 years STANDARD_DEVIATION 19.22 |
| Disease group Cogan's syndrome | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Disease group Giant Cell Arteritis | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Disease group IgA vasculitis | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 6 Participants |
| Disease group Polyarteritis Nodosa | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Disease group Relapsing Polychondritis | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Disease group Takayasu's Arteritis | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants | 3 Participants | 1 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 7 participants | 7 participants | 3 participants | 1 participants | 18 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 2 Participants | 1 Participants | 15 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 1 / 9 | 0 / 7 | 0 / 1 |
| other Total, other adverse events | 7 / 12 | 5 / 9 | 0 / 7 | 1 / 1 |
| serious Total, serious adverse events | 0 / 12 | 3 / 9 | 0 / 7 | 0 / 1 |
Outcome results
Primary
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.
Time frame: up to 720 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Treatment Failure | 5 treatment failures |
| Rituximab | Treatment Failure | 3 treatment failures |
| Tocilizumab | Treatment Failure | 1 treatment failures |
| Placebo | Treatment Failure | 0 treatment failures |
Secondary
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.
Time frame: 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
Population: Number analysed differs in each row depending on time in study for each participant.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Baseline | 1 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 240 | 1 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 600 | 0 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 360 | 1.5 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 120 | 1 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 720 | 0 score on a scale |
| Infliximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 480 | 2 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 360 | 3 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Baseline | 2 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 120 | 2 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 240 | 2 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 480 | 4 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 600 | 3 score on a scale |
| Rituximab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 720 | 4 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 480 | 3 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 600 | 3 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 120 | 2 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Baseline | 1 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 240 | 1.5 score on a scale |
| Tocilizumab | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 360 | 1.5 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 240 | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 120 | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 360 | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 480 | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Baseline | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 720 | 3 score on a scale |
| Placebo | Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment | Day 600 | 3 score on a scale |
Secondary
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
Time frame: up to 720 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab | Patients Achieving Response at Any 120 Day Timepoint | Day 600 | 1 Number of responders |
| Infliximab | Patients Achieving Response at Any 120 Day Timepoint | Day 360 | 3 Number of responders |
| Infliximab | Patients Achieving Response at Any 120 Day Timepoint | Day 720 | 0 Number of responders |
| Infliximab | Patients Achieving Response at Any 120 Day Timepoint | Day 480 | 2 Number of responders |
| Infliximab | Patients Achieving Response at Any 120 Day Timepoint | Day 240 | 6 Number of responders |
| Rituximab | Patients Achieving Response at Any 120 Day Timepoint | Day 480 | 1 Number of responders |
| Rituximab | Patients Achieving Response at Any 120 Day Timepoint | Day 600 | 1 Number of responders |
| Rituximab | Patients Achieving Response at Any 120 Day Timepoint | Day 720 | 1 Number of responders |
| Rituximab | Patients Achieving Response at Any 120 Day Timepoint | Day 360 | 4 Number of responders |
| Rituximab | Patients Achieving Response at Any 120 Day Timepoint | Day 240 | 4 Number of responders |
| Tocilizumab | Patients Achieving Response at Any 120 Day Timepoint | Day 480 | 1 Number of responders |
| Tocilizumab | Patients Achieving Response at Any 120 Day Timepoint | Day 240 | 2 Number of responders |
| Tocilizumab | Patients Achieving Response at Any 120 Day Timepoint | Day 360 | 2 Number of responders |
| Tocilizumab | Patients Achieving Response at Any 120 Day Timepoint | Day 600 | 1 Number of responders |
| Tocilizumab | Patients Achieving Response at Any 120 Day Timepoint | Day 720 | 0 Number of responders |
| Placebo | Patients Achieving Response at Any 120 Day Timepoint | Day 600 | 1 Number of responders |
| Placebo | Patients Achieving Response at Any 120 Day Timepoint | Day 360 | 1 Number of responders |
| Placebo | Patients Achieving Response at Any 120 Day Timepoint | Day 240 | 1 Number of responders |
| Placebo | Patients Achieving Response at Any 120 Day Timepoint | Day 480 | 1 Number of responders |
| Placebo | Patients Achieving Response at Any 120 Day Timepoint | Day 720 | 1 Number of responders |
Secondary
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
Time frame: 120 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP | 1 Participants |
| Rituximab | Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP | 5 Participants |
| Tocilizumab | Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP | 3 Participants |
| Placebo | Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP | 1 Participants |
Secondary
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.
Time frame: 120 days, 240 days, 360 days, 480 days, 600 days, 720 days
Population: Number analysed differs in each row depending on time in study for each participant
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Baseline | 2.5 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 240 | 1 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 600 | 1 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 360 | 1.5 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 120 | 3.5 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 720 | 0 score on a scale |
| Infliximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 480 | 2.5 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 360 | 2 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Baseline | 4 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 120 | 1.5 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 240 | 1 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 480 | 1 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 600 | 1 score on a scale |
| Rituximab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 720 | 1 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 480 | 1 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 600 | 1 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 120 | 1 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Baseline | 4 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 240 | 1 score on a scale |
| Tocilizumab | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 360 | 1 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 240 | 2 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 120 | 2 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 360 | 1 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 480 | 1 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Baseline | 5 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 720 | 1 score on a scale |
| Placebo | Physician's Global Assessment (PGA) (Likert Scale 0-10) | Day 600 | 1 score on a scale |
Secondary
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)
Time frame: up to 720 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | AESI | 21 Number of Events |
| Infliximab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | SAE | 0 Number of Events |
| Rituximab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | SAE | 0 Number of Events |
| Rituximab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | AESI | 2 Number of Events |
| Tocilizumab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | AESI | 17 Number of Events |
| Tocilizumab | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | SAE | 7 Number of Events |
| Placebo | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | AESI | 0 Number of Events |
| Placebo | Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs) | SAE | 0 Number of Events |