Low-dose Glucocorticoid Vasculitis Induction Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Low-dose Glucocorticoids Plus Rituximab Versus High-dose Glucocorticoids Plus Rituximab for Remission Induction in ANCA-associated Vasculitis; a Multicentre, Open Label, Randomised Control Trial

Conditions
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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Microscopic Polyangiitis, Wegener Granulomatosis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Glucocorticoids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent by a patient or a surrogate decision maker Age=>20 years 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 Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA Exclusion Criteria: Prior treatment for ANCA-associated vasculitis before trial entry ANCA-associated vasculitis related glomerulonephritis (eGFR<15ml/min) or alveolar hemorrhage (oxygen inhalation >2L/min) Presence of another multisystem autoimmune disease Known infection with HIV; a past or current history of hepatitis B virus or hepatitis C virus infection Desire to bear children, pregnancy or lactating History of malignancy within the past 5 years or any evidence of persistent malignancy Ongoing or recent (last 1 year) evidence of active tuberculosis Severe allergy or anaphylaxis to monoclonal antibody therapy Any concomitant condition anticipated to likely require oral systemic glucocorticoids, immunosuppressants, biologics, plasma exchange or IVIg Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months Other conditions, in the investigator's opinion, inappropriate for the trial entry

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose glucocorticoid<br>Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4). After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. | Drug: Rituximab<br>* Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.<br>* Other names: Rituxan;Drug: Glucocorticoids<br>* 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.<br>* Other names: Prednisolone;|
| Active Comparator: High-dose glucocorticoid<br>Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4). After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering. | Drug: Rituximab<br>* Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.<br>* Other names: Rituxan;Drug: Glucocorticoids<br>* 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.<br>* Other names: Prednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of the patients achieving remission | Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to remission | Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day | assessed at 1, 2, 4 and 6 months | 
| Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event | Assessed by Kaplan-Meier curves | 0-24 months | 
| Proportions of death, relapse, end-stage renal disease and the composite of these | Assessed by Kaplan-Meier curves | at 6 and 24 months | 
| Proportions of major relapse | major relapse is relapse with one or more BVAS major items | at 24 months | 
| Birmingham Vasculitis Activity Score (BVAS) version 3 | BVAS is a scoring system for assessing disease activity of vasculitis | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months | 
| Vasculitis Damage Index (VDI) | VDI is a scoring system for assessing irreversible disease damage due to vasculitis | assessed at 0, 6, 12, 18 and 24 months | 
| Short-Form 36 (SF-36) | SF-36 is a scoring system for assessing patient QOL. | assessed at 0, 6, 12, 18 and 24 months | 
| Patient global assessment (visualised analogue scale) | global assessments for disease activity and treatment toxicity | assessed at 0, 6, 12, 18 and 24 months | 
| Accumulative dose of glucocorticoids | Accumulative dose of glucocorticoids during the study period | assessed at 6 and 24 months | 
| Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events | Event numbers and proportion of the patients with one or more events are assessed. | at 6 and 24 months | 
| Proportions of the patients with new onset diabetes mellitus | diabetes mellitus requiring drug treatments | at 6 and 24 months | 
| Proportion of the patients with new onset insomnia | insomnia requiring drug treatments | at 6 and 24 months | 
| Proportion of the patients with new onset bone fracture, bone density | bone density is assessed at lumber spines | at 6 and 24 months | 
| Number of infections, proportions of the patients with infection | infections requiring drug treatments | at 6 and 24 months | 
| Proportions of the patients with new onset hypertension | hypertension requiring drug treatments | at 6 and 24 months | 
| Proportions of the patients with new onset hyperlipidemia | hyperlipidemia requiring drug treatments | at 6 and 24 months | 
| Proportions of patients achieving remission and discontinuance of glucocorticoids | Remission is BVAS ver3=0 and prednisolone <10mg/day. | at 6 and 24 months |