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| ID | Type | Description | Link |
|---|---|---|---|
| UMIN000014222 | Registry Identifier | UMIN-CTR |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low-dose glucocorticoid | Experimental | 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 | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase. |
|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Serum immunoglobulin levels | Serum immunoglobulin levels | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months |
| Peripheral blood B cell counts | CD19 positive B cells assessed by FACS |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hiroshi Nakajima, M.D., Ph.D | Chiba University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Asahi General Hospital | Asahi | Chiba | Japan | |||
| Kameda Medical Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12666064 | Background | 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. | |
| 19451574 | Background | 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. |
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| Type | Date | Date Unknown |
|---|---|---|
| Release | Jul 19, 2022 | |
| Reset | Jun 6, 2023 | |
| Release | Jun 7, 2023 | |
| Reset | Feb 7, 2024 |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Jul 19, 2022 | Jun 6, 2023 | |||
| Jun 7, 2023 |
| ID | Term |
|---|---|
| D056648 | Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis |
| D055953 | Microscopic Polyangiitis |
| D014890 | Granulomatosis with Polyangiitis |
| ID | Term |
|---|---|
| D056647 | Systemic Vasculitis |
| D014657 | Vasculitis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| D005938 | Glucocorticoids |
| D011239 | Prednisolone |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| Glucocorticoids | Drug | "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. |
|
|
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 |
| assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months |
| serum MPO-/PR3-ANCA levels measured by ELISA | MPO-ANCA and PR3-ANCA are disease specific autoantibodies binding neutrophil cytoplasmic antigen. | assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months |
| 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 |
| Teikyo University | tabashi City | Tokyo | Japan |
| Akita University | Akita | Japan |
| Chiba University Hospital | Chiba | 260-8677 | Japan |
| Chiba Aoba Municipal Hospital | Chiba | Japan |
| Chiba East Hospital | Chiba | Japan |
| Fukushima Medical University | Fukushima | Japan |
| Niigata University | Niigata | Japan |
| 16052573 | Background | 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. |
| 17582159 | Background | 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. |
| 5127139 | Background | 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. |
| 10329824 | Background | 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. |
| 20647199 | Background | 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. |
| 20647198 | Background | 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. |
| 21378402 | Background | 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. |
| 17429839 | Background | 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. |
| 20235186 | Background | 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. |
| 22174198 | Background | 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. |
| 24429174 | Background | 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. |
| 22729997 | Background | 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. |
| 23045170 | Background | 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. |
| 9041949 | Background | 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. |
| 37734880 | Derived | 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. |
| 34061144 | Derived | 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. |
| 33164993 | Derived | 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. |
| 29247107 | Derived | 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. |
| Feb 7, 2024 |
| D017445 |
| Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D059345 | Cerebral Small Vessel Diseases |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |