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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02198248
Other study ID # G25051
Secondary ID UMIN000014222
Status Active, not recruiting
Phase Phase 4
First received
Last updated
Start date October 2014
Est. completion date June 2021

Study information

Verified date January 2021
Source Chiba University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 140
Est. completion date June 2021
Est. primary completion date December 2019
Accepts healthy volunteers No
Gender All
Age group 20 Years and older
Eligibility 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


Related Conditions & MeSH terms


Intervention

Drug:
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.

Locations

Country Name City State
Japan Akita University Akita
Japan Asahi General Hospital Asahi Chiba
Japan Chiba Aoba Municipal Hospital Chiba
Japan Chiba East Hospital Chiba
Japan Chiba University Hospital Chiba
Japan Fukushima Medical University Fukushima
Japan Teikyo University Itabashi Tokyo
Japan Kameda Medical Centre Kamogawa Chiba
Japan Saitama Medical Center Kawagoe Saitama
Japan Matsudo City Hospital Matsudo Chiba
Japan Dokkyo Medical University Mibu Tochigi
Japan Japanese Red Cross Narita Hospital Narita Chiba
Japan Niigata University Niigata
Japan Hokkaido University Sapporo Hokkaido
Japan Keio University Hospital Shinanomachi Tokyo
Japan Yokohama Rosai Hospital Yokohama Kanagawa
Japan Shimoshizu Hospital Yotsukaido Chiba

Sponsors (1)

Lead Sponsor Collaborator
Chiba University

Country where clinical trial is conducted

Japan, 

References & Publications (16)

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. Review. — View Citation

Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dörner 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2007 Jun 20. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 16 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Other Serum immunoglobulin levels Serum immunoglobulin levels assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
Other Peripheral blood B cell counts CD19 positive B cells assessed by FACS assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
Other 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
Primary 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
Secondary 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
Secondary Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event Assessed by Kaplan-Meier curves 0-24 months
Secondary Proportions of death, relapse, end-stage renal disease and the composite of these Assessed by Kaplan-Meier curves at 6 and 24 months
Secondary Proportions of major relapse major relapse is relapse with one or more BVAS major items at 24 months
Secondary 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
Secondary 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
Secondary Short-Form 36 (SF-36) SF-36 is a scoring system for assessing patient QOL. assessed at 0, 6, 12, 18 and 24 months
Secondary Patient global assessment (visualised analogue scale) global assessments for disease activity and treatment toxicity assessed at 0, 6, 12, 18 and 24 months
Secondary Accumulative dose of glucocorticoids Accumulative dose of glucocorticoids during the study period assessed at 6 and 24 months
Secondary 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
Secondary Proportions of the patients with new onset diabetes mellitus diabetes mellitus requiring drug treatments at 6 and 24 months
Secondary Proportion of the patients with new onset insomnia insomnia requiring drug treatments at 6 and 24 months
Secondary Proportion of the patients with new onset bone fracture, bone density bone density is assessed at lumber spines at 6 and 24 months
Secondary Number of infections, proportions of the patients with infection infections requiring drug treatments at 6 and 24 months
Secondary Proportions of the patients with new onset hypertension hypertension requiring drug treatments at 6 and 24 months
Secondary Proportions of the patients with new onset hyperlipidemia hyperlipidemia requiring drug treatments at 6 and 24 months
Secondary Proportions of patients achieving remission and discontinuance of glucocorticoids Remission is BVAS ver3=0 and prednisolone <10mg/day. at 6 and 24 months
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