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Anti-Neutrophil Cytoplasmic Antibody-Associated VasculitisPhase 4LoVASNCT02198248

Low-dose Glucocorticoid Vasculitis Induction Study

A Phase 4 study testing Rituximab and Glucocorticoids in people with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis and Microscopic Polyangiitis, run by Chiba University at 17 sites in Japan.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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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. Read more about this study

Who is it for?
Ages 20 years and older
What is being tested?
Rituximab and Glucocorticoids
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
140 participants
Where
17 sitesJapan
Study dates
Oct 2014to Jun 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

Japan17 sites

  • Akita University

    Akita

  • Asahi General Hospital

    Asahi, Chiba

  • Chiba University Hospital

    Chiba, 260-8677

  • Chiba Aoba Municipal Hospital

    Chiba

  • Chiba East Hospital

    Chiba

  • Fukushima Medical University

    Fukushima

  • Kameda Medical Centre

    Kamogawa, Chiba

  • Saitama Medical Center

    Kawagoe, Saitama

  • Matsudo City Hospital

    Matsudo, Chiba

  • Dokkyo Medical University

    Mibu, Tochigi

  • Japanese Red Cross Narita Hospital

    Narita, Chiba

  • Niigata University

    Niigata

  • Hokkaido University

    Sapporo, Hokkaido

  • Keio University Hospital

    Shinanomachi, Tokyo

  • Teikyo University

    tabashi City, Tokyo

  • Yokohama Rosai Hospital

    Yokohama, Kanagawa

  • Shimoshizu Hospital

    Yotsukaidō, Chiba

Other trials in Japan

About this study

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

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.

Read more

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.

Read the detailed 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.

Being tested
Rituximab, Glucocorticoids
Medical subject headings
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Microscopic Polyangiitis, Granulomatosis with Polyangiitis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RituximabDrug

    Also called Rituxan

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

  • GlucocorticoidsDrug

    Also called Predonine, Prednisolone

    "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.

Study groups in NCT02198248
Study groupRoleWhat they receive
Low-dose glucocorticoidExperimentalPrednisolone 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.
Receives: Drug: Rituximab; Drug: Glucocorticoids
High-dose glucocorticoidActive comparatorPrednisolone 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.
Receives: Drug: Rituximab; Drug: Glucocorticoids

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 6 months

Secondary outcomes (17)

  1. Time to remission

    Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day

    Measured: assessed at 1, 2, 4 and 6 months

  2. Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event

    Assessed by Kaplan-Meier curves

    Measured: 0-24 months

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

    Assessed by Kaplan-Meier curves

    Measured: at 6 and 24 months

  4. Proportions of major relapse

    major relapse is relapse with one or more BVAS major items

    Measured: at 24 months

  5. Birmingham Vasculitis Activity Score (BVAS) version 3

    BVAS is a scoring system for assessing disease activity of vasculitis

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

  6. Vasculitis Damage Index (VDI)

    VDI is a scoring system for assessing irreversible disease damage due to vasculitis

    Measured: assessed at 0, 6, 12, 18 and 24 months

  7. Short-Form 36 (SF-36)

    SF-36 is a scoring system for assessing patient QOL.

    Measured: assessed at 0, 6, 12, 18 and 24 months

  8. Patient global assessment (visualised analogue scale)

    global assessments for disease activity and treatment toxicity

    Measured: assessed at 0, 6, 12, 18 and 24 months

  9. Accumulative dose of glucocorticoids

    Accumulative dose of glucocorticoids during the study period

    Measured: assessed at 6 and 24 months

  10. 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.

    Measured: at 6 and 24 months

  11. Proportions of the patients with new onset diabetes mellitus

    diabetes mellitus requiring drug treatments

    Measured: at 6 and 24 months

  12. Proportion of the patients with new onset insomnia

    insomnia requiring drug treatments

    Measured: at 6 and 24 months

  13. Proportion of the patients with new onset bone fracture, bone density

    bone density is assessed at lumber spines

    Measured: at 6 and 24 months

  14. Number of infections, proportions of the patients with infection

    infections requiring drug treatments

    Measured: at 6 and 24 months

  15. Proportions of the patients with new onset hypertension

    hypertension requiring drug treatments

    Measured: at 6 and 24 months

  16. Proportions of the patients with new onset hyperlipidemia

    hyperlipidemia requiring drug treatments

    Measured: at 6 and 24 months

  17. Proportions of patients achieving remission and discontinuance of glucocorticoids

    Remission is BVAS ver3=0 and prednisolone <10mg/day.

    Measured: at 6 and 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jul 2014 (estimated)
  2. Study startOct 2014
  3. Primary completionDec 2019
  4. Study completionJun 2021 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
140 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02198248
Sponsor's protocol ID
G25051
Other IDs
UMIN000014222
Acronym
LoVAS
Status last verified
Jan 2021
First submitted
18 Jul 2014
Last updated
27 Jan 2021
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 12666064

  • 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.

    PubMed 19451574

  • 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.

    PubMed 16052573

  • 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.

    PubMed 17582159

  • 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.

    PubMed 5127139

  • 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.

    PubMed 10329824

  • 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.

    PubMed 20647199

  • 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.

    PubMed 20647198

  • 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.

    PubMed 21378402

  • 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.

    PubMed 17429839

  • 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.

    PubMed 20235186

  • 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.

    PubMed 22174198

  • 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.

    PubMed 24429174

  • 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.

    PubMed 22729997

  • 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.

    PubMed 23045170

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Rituximab and Glucocorticoids in people with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis and Microscopic Polyangiitis, run by Chiba University at 17 sites in Japan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 27 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of the patients achieving remission (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02198248, which also lists 20 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2021.

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