Low-dose Glucocorticoid Vasculitis Induction Study

Phase 4

• Conditions: Wegener Granulomatosis; Microscopic Polyangiitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Interventions: Drug: Rituximab; Drug: Glucocorticoids

• Registration Number: NCT02198248
• Lead Sponsor: Chiba University

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.

Study Timeline

• Study First Submitted: 2014-07-18
• Study First Submitted QC: 2014-07-21
• Study First Posted: 2014-07-23
• Study Start: 2014-10
• Primary Completion: 2019-12
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-25
• Last Update Posted: 2021-01-27
• Study Completion: 2021-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 140

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low-dose glucocorticoid	Glucocorticoids	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.
High-dose glucocorticoid	Glucocorticoids	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.
Low-dose glucocorticoid	Rituximab	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.
High-dose glucocorticoid	Rituximab	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Proportions of the patients with new onset hypertension	at 6 and 24 months	hypertension 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
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
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.
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
Short-Form 36 (SF-36)	assessed at 0, 6, 12, 18 and 24 months	SF-36 is a scoring system for assessing patient QOL.
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 diabetes mellitus	at 6 and 24 months	diabetes mellitus 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
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
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
Proportion of the patients with new onset insomnia	at 6 and 24 months	insomnia requiring drug treatments
Proportions of the patients with new onset hyperlipidemia	at 6 and 24 months	hyperlipidemia requiring drug treatments
Number of infections, proportions of the patients with infection	at 6 and 24 months	infections requiring drug treatments

Trial Locations

Locations (17)

Yokohama Rosai Hospital; 🇯🇵 Yokohama, Kanagawa, Japan

Saitama Medical Center; 🇯🇵 Kawagoe, Saitama, Japan

Dokkyo Medical University; 🇯🇵 Mibu, Tochigi, Japan

Teikyo University; 🇯🇵 Itabashi, Tokyo, Japan

Akita University; 🇯🇵 Akita, Japan

Chiba University Hospital; 🇯🇵 Chiba, Japan

Chiba Aoba Municipal Hospital; 🇯🇵 Chiba, Japan

Chiba East Hospital; 🇯🇵 Chiba, Japan

Niigata University; 🇯🇵 Niigata, Japan

Asahi General Hospital; 🇯🇵 Asahi, Chiba, Japan

Matsudo City Hospital; 🇯🇵 Matsudo, Chiba, Japan

Japanese Red Cross Narita Hospital; 🇯🇵 Narita, Chiba, Japan

Shimoshizu Hospital; 🇯🇵 Yotsukaido, Chiba, Japan

Hokkaido University; 🇯🇵 Sapporo, Hokkaido, Japan

Keio University Hospital; 🇯🇵 Shinanomachi, Tokyo, Japan

Fukushima Medical University; 🇯🇵 Fukushima, Japan

Kameda Medical Centre; 🇯🇵 Kamogawa, Chiba, Japan