Low-dose Glucocorticoid Vasculitis Induction Study

Microscopic Polyangiitis Clinical Trial

— LoVAS  

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

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
• 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
• 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

Related Conditions & MeSH terms

• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Granulomatosis with Polyangiitis
• Microscopic Polyangiitis
• Vasculitis
• Wegener Granulomatosis

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 all — Click 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