Low-dose Glucocorticoid Vasculitis Induction Study

NCT02198248 | Unknown Phase 4 DMC

• 2 other identifiers: G25051UMIN000014222
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 17

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.

Conditions

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Wegener Granulomatosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (17)

• Time to remission

  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

  0-24 months

• Proportions of death, relapse, end-stage renal disease and the composite of these

  at 6 and 24 months

• Proportions of major relapse

  at 24 months

• Birmingham Vasculitis Activity Score (BVAS) version 3

  assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months

Other Outcomes (3)

• Serum immunoglobulin levels

  assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months

• Peripheral blood B cell counts

  assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months

• serum MPO-/PR3-ANCA levels measured by ELISA

  assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months

Study Arms (2)

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.

Drug: Rituximab; Drug: Glucocorticoids

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.

Drug: Rituximab; Drug: Glucocorticoids

Interventions

Rituximab DRUG

Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.

Also known as: Rituxan

High-dose glucocorticoid; Low-dose glucocorticoid

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.

Also known as: Predonine, Prednisolone

High-dose glucocorticoid; Low-dose glucocorticoid

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent by a patient or a surrogate decision maker
• Age=\>20 years
• 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
• Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA

You may not qualify if:

• Prior treatment for ANCA-associated vasculitis before trial entry
• ANCA-associated vasculitis related glomerulonephritis (eGFR\<15ml/min) or alveolar hemorrhage (oxygen inhalation \>2L/min)
• Presence of another multisystem autoimmune disease
• Known infection with HIV; a past or current history of hepatitis B virus or hepatitis C virus infection
• Desire to bear children, pregnancy or lactating
• History of malignancy within the past 5 years or any evidence of persistent malignancy
• Ongoing or recent (last 1 year) evidence of active tuberculosis
• Severe allergy or anaphylaxis to monoclonal antibody therapy
• Any concomitant condition anticipated to likely require oral systemic glucocorticoids, immunosuppressants, biologics, plasma exchange or IVIg
• Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months
• Other conditions, in the investigator's opinion, inappropriate for the trial entry

Sponsors & Collaborators

• Chiba University: lead

Study Sites (17)

Asahi General Hospital

Asahi, Chiba, Japan

Location

Kameda Medical Centre

Kamogawa, Chiba, Japan

Location

Matsudo City Hospital

Matsudo, Chiba, Japan

Location

Japanese Red Cross Narita Hospital

Narita, Chiba, Japan

Location

Shimoshizu Hospital

Yotsukaidō, Chiba, Japan

Location

Hokkaido University

Sapporo, Hokkaido, Japan

Location

Yokohama Rosai Hospital

Yokohama, Kanagawa, Japan

Location

Saitama Medical Center

Kawagoe, Saitama, Japan

Location

Dokkyo Medical University

Mibu, Tochigi, Japan

Location

Keio University Hospital

Shinanomachi, Tokyo, Japan

Location

Teikyo University

tabashi City, Tokyo, Japan

Location

Akita University

Akita, Japan

Location

Chiba University Hospital

Chiba, 260-8677, Japan

Location

Chiba Aoba Municipal Hospital

Chiba, Japan

Location

Chiba East Hospital

Chiba, Japan

Location

Fukushima Medical University

Fukushima, Japan

Location

Niigata University

Niigata, Japan

Location

Related Publications (20)

• 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.

  PMID: 12666064 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.

  PMID: 19451574 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.

  PMID: 16052573 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.

  PMID: 17582159 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.

  PMID: 5127139 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.

  PMID: 10329824 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.

  PMID: 20647199 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.

  PMID: 20647198 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.

  PMID: 21378402 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.

  PMID: 17429839 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.

  PMID: 20235186 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.

  PMID: 22174198 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.

  PMID: 24429174 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.

  PMID: 22729997 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.

  PMID: 23045170 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.

  PMID: 9041949 BACKGROUND

• 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.

  PMID: 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. 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.

  PMID: 34061144 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.

  PMID: 33164993 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.

  PMID: 29247107 DERIVED

MeSH Terms

Conditions

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Granulomatosis with Polyangiitis

Interventions

Rituximab; Glucocorticoids; Prednisolone

Condition Hierarchy (Ancestors)

Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Hiroshi Nakajima, M.D., Ph.D

  Chiba University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 18, 2014
• First Posted: July 23, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2019
• Study Completion: June 1, 2021
• Last Updated: January 27, 2021

Record last verified: 2021-01

Locations

JP (17)