Study Results
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Basic Information
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UNKNOWN
PHASE4
140 participants
INTERVENTIONAL
2014-10-31
2021-06-30
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Low-dose glucocorticoid
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.
Rituximab
Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
Glucocorticoids
"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.
High-dose glucocorticoid
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.
Rituximab
Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
Glucocorticoids
"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.
Interventions
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Rituximab
Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
Glucocorticoids
"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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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
20 Years
ALL
No
Sponsors
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Chiba University
OTHER
Responsible Party
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Shunsuke Furuta
Associate Professor
Principal Investigators
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Hiroshi Nakajima, M.D., Ph.D
Role: PRINCIPAL_INVESTIGATOR
Chiba University Hospital
Locations
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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
YotsukaidÅ, 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
Teikyo University
tabashi City, Tokyo, Japan
Akita University
Akita, , Japan
Chiba University Hospital
Chiba, , Japan
Chiba Aoba Municipal Hospital
Chiba, , Japan
Chiba East Hospital
Chiba, , Japan
Fukushima Medical University
Fukushima, , Japan
Niigata University
Niigata, , Japan
Countries
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References
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Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD, Jayne DR; Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003 Apr;41(4):776-84. doi: 10.1016/s0272-6386(03)00025-8.
de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004.
De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/art.21142.
Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, Mirapeix E, Savage CO, Sinico RA, Stegeman CA, Westman KW, van der Woude FJ, de Lind van Wijngaarden RA, Pusey CD; European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8. doi: 10.1681/ASN.2007010090. Epub 2007 Jun 20.
Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response in Wegener's granulomatosis. N Engl J Med. 1971 Dec 30;285(27):1493-6. doi: 10.1056/NEJM197112302852701. No abstract available.
Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Differential B- and T-cell activation in Wegener's granulomatosis. J Allergy Clin Immunol. 1999 May;103(5 Pt 1):885-94. doi: 10.1016/s0091-6749(99)70434-3.
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169.
Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T, Ferraccioli G, Gottenberg JE, Isaacs J, Kvien TK, Mariette X, Martin-Mola E, Pavelka K, Tak PP, van der Heijde D, van Vollenhoven RF, Emery P; Rituximab Consensus Expert Committee. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011 Jun;70(6):909-20. doi: 10.1136/ard.2010.144998. Epub 2011 Mar 6.
Rafailidis PI, Kakisi OK, Vardakas K, Falagas ME. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials. Cancer. 2007 Jun 1;109(11):2182-9. doi: 10.1002/cncr.22666.
Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis. Arthritis Care Res (Hoboken). 2010 Aug;62(8):1166-73. doi: 10.1002/acr.20176.
Wada T, Hara A, Arimura Y, Sada KE, Makino H; Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan. Risk factors associated with relapse in Japanese patients with microscopic polyangiitis. J Rheumatol. 2012 Mar;39(3):545-51. doi: 10.3899/jrheum.110705. Epub 2011 Dec 15.
Furuta S, Chaudhry AN, Hamano Y, Fujimoto S, Nagafuchi H, Makino H, Matsuo S, Ozaki S, Endo T, Muso E, Ito C, Kusano E, Yamagata M, Ikeda K, Kashiwakuma D, Iwamoto I, Westman K, Jayne D. Comparison of phenotype and outcome in microscopic polyangiitis between Europe and Japan. J Rheumatol. 2014 Feb;41(2):325-33. doi: 10.3899/jrheum.130602. Epub 2014 Jan 15.
Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, Jayne DR. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Nov;64(11):3760-9. doi: 10.1002/art.34583.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715. No abstract available.
Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, Adu D. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997 Feb;40(2):371-80. doi: 10.1002/art.1780400222.
Furuta S, Nakagomi D, Kobayashi Y, Hiraguri M, Sugiyama T, Amano K, Umibe T, Kono H, Kurasawa K, Kita Y, Matsumura R, Kaneko Y, Ninagawa K, Hiromura K, Kagami SI, Inaba Y, Hanaoka H, Ikeda K, Nakajima H; LoVAS collaborators. Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study. Ann Rheum Dis. 2024 Jan 2;83(1):96-102. doi: 10.1136/ard-2023-224343.
Furuta S, Nakagomi D, Kobayashi Y, Hiraguri M, Sugiyama T, Amano K, Umibe T, Kono H, Kurasawa K, Kita Y, Matsumura R, Kaneko Y, Ninagawa K, Hiromura K, Kagami SI, Inaba Y, Hanaoka H, Ikeda K, Nakajima H; LoVAS Collaborators. Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial. JAMA. 2021 Jun 1;325(21):2178-2187. doi: 10.1001/jama.2021.6615.
Serling-Boyd N, Wallace ZS. Management of primary vasculitides with biologic and novel small molecule medications. Curr Opin Rheumatol. 2021 Jan;33(1):8-14. doi: 10.1097/BOR.0000000000000756.
Furuta S, Sugiyama T, Umibe T, Kaneko Y, Amano K, Kurasawa K, Nakagomi D, Hiraguri M, Hanaoka H, Sato Y, Ikeda K, Nakajima H; LoVAS Trial study investigators. Low-dose glucocorticoids plus rituximab versus high-dose glucocorticoids plus rituximab for remission induction in ANCA-associated vasculitis (LoVAS): protocol for a multicentre, open-label, randomised controlled trial. BMJ Open. 2017 Dec 14;7(12):e018748. doi: 10.1136/bmjopen-2017-018748.
Other Identifiers
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UMIN000014222
Identifier Type: REGISTRY
Identifier Source: secondary_id
G25051
Identifier Type: -
Identifier Source: org_study_id
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