| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Non-ANCA associated vasculitides:
1. Giant cell arteritis (GCA)
2. Takayasu’s arteritis (TA)
3. Polyarteritis nodosa (PAN) or cutaneous polyarteritis unrelated to hepatitis B (CPAN)
4. Relapsing polychondritis (RP)
5. IgA vasculitis (IgAV)
6. Cogan’s syndrome
7. Non-infective cryoglobulinaemia
8. Primary angiitis of central nervous system (PACNS)
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| E.1.1.1 | Medical condition in easily understood language |
| An autoimmune disease in which blood vessels are inflamed due to overactive defence mechanisms which usually protect against infection. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10047115 |
| E.1.2 | Term | Vasculitis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| How clinically effective are the following biologic treatments: Infliximab, Rituximab and Tocilizumab compared to placebo in treating refractory non-ANCA associated vasculitis? |
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| E.2.2 | Secondary objectives of the trial |
| How safe, clinically effective and cost-effective are these treatments in comparison to each other and placebo? |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
4. Refractory disease defined by:
- Active disease, BVAS v3 modified for BIOVAS (BVAS v3-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
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| E.4 | Principal 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 plasma exchange or intravenous immunoglobulins within 30 days, or cyclophosphamide or lymphocyte depleting biologic (e.g. rituximab) within 6 months of screening visit
4. Have an active systemic bacterial, viral or fungal infection, or active/latent tuberculosis
5. Hepatitis B (HB) core antibody (Ab) or HB surface antigen positive or hepatitis C antibody positive or human immunodeficiency virus (HIV) antibody test positive
6. 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
7. Pregnant or breastfeeding
8. Severe disease, which in the opinion of the physician prevents randomisation to placebo
9. Recent or upcoming major surgery within 45 days of screening visit
10. Leukocyte count < 3.5 x 10^9, platelet count < 100 x 10^9 cells/l, neutrophil count of < 1 x 10^9 cells/l
11. ALT or ALP > 3 times the upper limit of normal
12. Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication within 90 days of screening visit
13. Demyelinating disorders
14. 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
15. Administration of live or live attenuated vaccines within 45 days of screening
16. Participation in any clinical trial of an investigational medicinal product within 30 days prior to screening or within 5 half-lives after taking the last dose
17. Diagnosis of adenosine deaminase type 2 (DADA2)
18. Hypersensitivity to the active IMP substance or to any of the formulation excipients |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcome is time to treatment failure (TTF).
TTF for each IMP is the time from the start of IMP treatment, to treatment failure (see definitions below) or the end of trial participation (censored).
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 BIVOAS (BVAS v3-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.
Secondary treatment failure is defined as having achieved response by 120 days from IMP commencement, with subsequent relapse (see definitions below) after 120 days from IMP commencement.
If an adverse reaction to an IMP precludes the participant from receiving further doses of the trial drug, this will also be considered a secondary treatment failure .
The primary outcome for each active IMP is pooled across all participants in the primary group and compared against placebo.
Response is defined by:
Absence of new/worse BVAS v3 modified for BIOVAS (BVAS v3-BIOVAS) (adults) / PVAS (children) items assessed at the 120 day evaluation time points after commencing IMP AND
Prednisolone ≤ 10mg/day or ≤ 0.2 mg/kg for children (whichever is lower), unless the baseline dose is < 10mg/day or < 0.2 mg/kg children (whichever is lower) in which case it should not be more than the baseline dose*.
* Baseline dose is the dose of oral prednisolone, mg/day, or equivalent steroid, averaged over the 7 days prior to the start of each new IMP .
Relapse is defined by either:
Appearance of ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) BVAS v3 BIOVAS/PVAS items from the time of BVAS response (as defined above) assessed at the 120 day evaluation time points# OR
The need to increase the dose of prednisolone to > 20mg/day to treat vasculitis OR
The need to increase the dose of an immunomodulator or immune-suppressive therapy in order to treat vasculitis
# Non-severe items can be upgraded by the investigator to severe based on their potential clinical impact, e.g. headache in GCA, thus could meet failure criteria if only one or two items are present.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Participants will be assessed for primary outcome measure every 120 days. |
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| E.5.2 | Secondary end point(s) |
1. Bayesian hierarchical priors elicitation for treatment effects of biologics compared to placebo and biologics against each other in 2 groups: large vessel vasculitis (GCA/TA) and all other NAAV subgroups in the study
2. Proportion of patients achieving response at 120 days evaluation after the start of each intervention.
3. Proportion of patients achieving response at 120 days defined by a BVAS v3/ PVAS of ≤ one non-severe (no new/worse) item, prednisolone dose ≤ 50% of the dose at the start of the intervention and ≤ 10mg/day (0.2 mg/kg/day for children, whichever is lower) and an ESR < 30mm/hr or CRP <10 mg/L
4. Increase in disease related damage measured by VDI/PVDI from start to end of an IMP block
5. Physician’s global assessment (PGA) (Likert scale 0-10) every 120 days
6. Serious adverse events/Serious adverse reactions (SAEs/SARs)
7. EQ-5D-5L or Child Health Utility (CHU9D) assessments every 120 days |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Participants will be assessed for secondary outcome measures every 120 days. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 24 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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