Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Microscopic Polyangiitis, Wegener Granulomatosis
Conditions
Brief summary
Previous reports suggested conventional immunosuppressants such as cyclophosphamide could not reduce glucocorticoid dose in remission induction in ANCA-associated vasculitis because of lower remission rate and higher relapse rate. However those reports didn't include rituximab. B cell depletion therapy by rituximab is a new strategy for remission induction in ANCA-associated vasculitis. The RAVE and RITUXVAS trial (NEJM 2010, both) showed high-dose glucocorticoid plus rituximab had roughly the same efficacy and safety as high-dose glucocorticoid plus IV-cyclophosphamide. In addition, recent retrospective observational studies reported low-dose glucocorticoid plus rituximab led to re-induction in severe relapsing ANCA-associated vasculitis. Thus, the investigators aim to investigate whether rituximab can reduce glucocorticoid dose in induction remission in ANCA-associated vasculitis (to show non-inferiority for efficacy between low-dose and high-dose glucocorticoid plus rituximab). Participants will be randomised to the low-dose glucocorticoid plus rituximab or the high-dose glucocorticoid plus rituximab groups. Primary endpoint is proportion of remission at 6 months, then data regarding relapse and long-term safety will be collected until 24 months. The study has been designed by the principal and coordinating investigators. It will include 140 participants from 18 hospitals in Japan. It is funded by Chiba University Hospital and Chiba East Hospital.
Detailed description
ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is characterised by small vessel vasculitis and presence of autoantibodies, ANCA. It can be a life-threatening disease with renal/respiratory failure. Current standard therapy in induction remission for ANCA-associated vasculitis is combination of high-dose glucocorticoid and IV-cyclophosphamide. This regimen is effective (remission rate; 80-90%), but often cause various glucocorticoid-related side effects. Especially, infection is related to death. Thus a new regimen reducing glucocorticoid dose is required.
Interventions
DRUGRituximab
Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
DRUGGlucocorticoids
Low-dose group commenced 0.5mg/kg/day, then taper and stop within 6 months following pre-defined schedule. High-dose group commenced 1.0mg/kg/day, then taper to 10mg/day within 6 months following pre-defined schedule.
Sponsors
Chiba University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent by a patient or a surrogate decision maker 2. Age=\>20 years 3. New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis or renal limited ANCA-associated vasculitis) consistent with the 2012 Chapel Hill consensus definitions 4. Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA
Exclusion criteria
1. Prior treatment for ANCA-associated vasculitis before trial entry 2. ANCA-associated vasculitis related glomerulonephritis (eGFR\<15ml/min) or alveolar hemorrhage (oxygen inhalation \>2L/min) 3. Presence of another multisystem autoimmune disease 4. Known infection with HIV; a past or current history of hepatitis B virus or hepatitis C virus infection 5. Desire to bear children, pregnancy or lactating 6. History of malignancy within the past 5 years or any evidence of persistent malignancy 7. Ongoing or recent (last 1 year) evidence of active tuberculosis 8. Severe allergy or anaphylaxis to monoclonal antibody therapy 9. Any concomitant condition anticipated to likely require oral systemic glucocorticoids, immunosuppressants, biologics, plasma exchange or IVIg 10. Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months 11. Other conditions, in the investigator's opinion, inappropriate for the trial entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of the patients achieving remission | 6 months | Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone \<10mg/day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient global assessment (visualised analogue scale) | assessed at 0, 6, 12, 18 and 24 months | global assessments for disease activity and treatment toxicity |
| Proportions of the patients with new onset hypertension | at 6 and 24 months | hypertension requiring drug treatments |
| Proportions of the patients with new onset hyperlipidemia | at 6 and 24 months | hyperlipidemia requiring drug treatments |
| Proportions of patients achieving remission and discontinuance of glucocorticoids | at 6 and 24 months | Remission is BVAS ver3=0 and prednisolone \<10mg/day. |
| Time to remission | assessed at 1, 2, 4 and 6 months | Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone \<10mg/day |
| Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event | 0-24 months | Assessed by Kaplan-Meier curves |
| Proportions of death, relapse, end-stage renal disease and the composite of these | at 6 and 24 months | Assessed by Kaplan-Meier curves |
| Proportions of major relapse | at 24 months | major relapse is relapse with one or more BVAS major items |
| Birmingham Vasculitis Activity Score (BVAS) version 3 | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months | BVAS is a scoring system for assessing disease activity of vasculitis |
| Vasculitis Damage Index (VDI) | assessed at 0, 6, 12, 18 and 24 months | VDI is a scoring system for assessing irreversible disease damage due to vasculitis |
| Short-Form 36 (SF-36) | assessed at 0, 6, 12, 18 and 24 months | SF-36 is a scoring system for assessing patient QOL. |
| Accumulative dose of glucocorticoids | assessed at 6 and 24 months | Accumulative dose of glucocorticoids during the study period |
| Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events | at 6 and 24 months | Event numbers and proportion of the patients with one or more events are assessed. |
| Proportions of the patients with new onset diabetes mellitus | at 6 and 24 months | diabetes mellitus requiring drug treatments |
| Proportion of the patients with new onset insomnia | at 6 and 24 months | insomnia requiring drug treatments |
| Proportion of the patients with new onset bone fracture, bone density | at 6 and 24 months | bone density is assessed at lumber spines |
| Number of infections, proportions of the patients with infection | at 6 and 24 months | infections requiring drug treatments |
Other
| Measure | Time frame | Description |
|---|---|---|
| serum MPO-/PR3-ANCA levels measured by ELISA | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months | MPO-ANCA and PR3-ANCA are disease specific autoantibodies binding neutrophil cytoplasmic antigen. |
| Peripheral blood B cell counts | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months | CD19 positive B cells assessed by FACS |
| Serum immunoglobulin levels | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months | Serum immunoglobulin levels |
Countries
Japan
Outcome results
None listed