Low-dose Glucocorticoid Vasculitis Induction Study

Phase 4UnknownNCT02198248

Chiba University140 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

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

Locations (17)

Asahi General Hospital

Asahi, Chiba, Japan

Kameda Medical Centre

Kamogawa, Chiba, Japan

Matsudo City Hospital

Matsudo, Chiba, Japan

Japanese Red Cross Narita Hospital

Narita, Chiba, Japan

Shimoshizu Hospital

Yotsukaidō, Chiba, Japan

Hokkaido University

Sapporo, Hokkaido, Japan

Yokohama Rosai Hospital

Yokohama, Kanagawa, Japan

Saitama Medical Center

Kawagoe, Saitama, Japan

Dokkyo Medical University

Mibu, Tochigi, Japan

Keio University Hospital

Shinanomachi, Tokyo, Japan

...and 7 more locations

Outcomes

Primary Outcomes

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

Time frame: 6 months

Secondary Outcomes

Time to remission

Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone \<10mg/day

Time frame: 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

Time frame: 0-24 months

Proportions of death, relapse, end-stage renal disease and the composite of these

Assessed by Kaplan-Meier curves

Time frame: at 6 and 24 months

Proportions of major relapse

major relapse is relapse with one or more BVAS major items

Time frame: at 24 months

Birmingham Vasculitis Activity Score (BVAS) version 3

BVAS is a scoring system for assessing disease activity of vasculitis

Time frame: 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

Time frame: assessed at 0, 6, 12, 18 and 24 months

Short-Form 36 (SF-36)

SF-36 is a scoring system for assessing patient QOL.

Time frame: assessed at 0, 6, 12, 18 and 24 months

Patient global assessment (visualised analogue scale)

global assessments for disease activity and treatment toxicity

Time frame: assessed at 0, 6, 12, 18 and 24 months

Accumulative dose of glucocorticoids

Accumulative dose of glucocorticoids during the study period

Time frame: 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.

Time frame: at 6 and 24 months

Proportions of the patients with new onset diabetes mellitus

diabetes mellitus requiring drug treatments

Time frame: at 6 and 24 months

Proportion of the patients with new onset insomnia

insomnia requiring drug treatments

Time frame: at 6 and 24 months

Proportion of the patients with new onset bone fracture, bone density

bone density is assessed at lumber spines

Time frame: at 6 and 24 months

Number of infections, proportions of the patients with infection

infections requiring drug treatments

Time frame: at 6 and 24 months

Proportions of the patients with new onset hypertension

hypertension requiring drug treatments

Time frame: at 6 and 24 months

Proportions of the patients with new onset hyperlipidemia

hyperlipidemia requiring drug treatments

Time frame: at 6 and 24 months

Proportions of patients achieving remission and discontinuance of glucocorticoids

Remission is BVAS ver3=0 and prednisolone \<10mg/day.

Time frame: at 6 and 24 months

Low-dose Glucocorticoid Vasculitis Induction Study

Overview

Conditions

Interventions

Eligibility

Locations (17)

Outcomes

Primary Outcomes

Secondary Outcomes