Clinical trial NCT02198248: Low-dose Glucocorticoid Vasculitis Induction Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Microscopic Polyangiitis
Wegener Granulomatosis
Lead sponsor: Chiba University
Sponsor class: OTHER
First posted: 2014-07-23
Enrollment: 140
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of the patients achieving remission
timeFrame: 6 months
Secondary outcomes:
measure: Time to remission
timeFrame: assessed at 1, 2, 4 and 6 months
measure: Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event
timeFrame: 0-24 months
measure: Proportions of death, relapse, end-stage renal disease and the composite of these
timeFrame: at 6 and 24 months
measure: Proportions of major relapse
timeFrame: at 24 months
measure: Birmingham Vasculitis Activity Score (BVAS) version 3
timeFrame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
measure: Vasculitis Damage Index (VDI)
timeFrame: assessed at 0, 6, 12, 18 and 24 months
measure: Short-Form 36 (SF-36)
timeFrame: assessed at 0, 6, 12, 18 and 24 months
measure: Patient global assessment (visualised analogue scale)
timeFrame: assessed at 0, 6, 12, 18 and 24 months
measure: Accumulative dose of glucocorticoids
timeFrame: assessed at 6 and 24 months
measure: Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events
timeFrame: at 6 and 24 months
measure: Proportions of the patients with new onset diabetes mellitus
timeFrame: at 6 and 24 months
measure: Proportion of the patients with new onset insomnia
timeFrame: at 6 and 24 months
measure: Proportion of the patients with new onset bone fracture, bone density
timeFrame: at 6 and 24 months
measure: Number of infections, proportions of the patients with infection
timeFrame: at 6 and 24 months
measure: Proportions of the patients with new onset hypertension
timeFrame: at 6 and 24 months
measure: Proportions of the patients with new onset hyperlipidemia
timeFrame: at 6 and 24 months
measure: Proportions of patients achieving remission and discontinuance of glucocorticoids
timeFrame: at 6 and 24 months
Other outcomes:
measure: Serum immunoglobulin levels
timeFrame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
measure: Peripheral blood B cell counts
timeFrame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
measure: serum MPO-/PR3-ANCA levels measured by ELISA
timeFrame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
Locations:
city: Asahi
country: Japan
facility: Asahi General Hospital
state: Chiba
city: Kamogawa
country: Japan
facility: Kameda Medical Centre
state: Chiba
city: Matsudo
country: Japan
facility: Matsudo City Hospital
state: Chiba
city: Narita
country: Japan
facility: Japanese Red Cross Narita Hospital
state: Chiba
city: Yotsukaido
country: Japan
facility: Shimoshizu Hospital
state: Chiba
city: Sapporo
country: Japan
facility: Hokkaido University
state: Hokkaido
city: Yokohama
country: Japan
facility: Yokohama Rosai Hospital
state: Kanagawa
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Mibu
country: Japan
facility: Dokkyo Medical University
state: Tochigi
city: Itabashi
country: Japan
facility: Teikyo University
state: Tokyo
city: Shinanomachi
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Akita
country: Japan
facility: Akita University
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Chiba
country: Japan
facility: Chiba Aoba Municipal Hospital
city: Chiba
country: Japan
facility: Chiba East Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University
city: Niigata
country: Japan
facility: Niigata University
Study officials:
affiliation: Chiba University Hospital
name: Hiroshi Nakajima, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
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