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Rituximab Vasculitis Maintenance Study

Information source: Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Wegener Granulomatosis

Intervention: Rituximab (Biological); Azathioprine (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Cambridge University Hospitals NHS Foundation Trust

Official(s) and/or principal investigator(s):
David Jayne, Study Chair, Affiliation: Cambridge University Hospitals NHS Foundation Trust
Peter Merkel, Study Chair, Affiliation: University of Pennsylvania

Overall contact:
David Jayne, Email: dj106@cam.ac.uk

Summary

Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its effect wears off and the disease can return. This occurs in at least half of patients within 2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating rituximab every six months stops the disease returning and is safe. The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and whether it works better than the older treatments, azathioprine or methotrexate. It will also tell us how long patients remain well after the repeated rituximab treatments are stopped, and if repeated rituximab is safe. We should also learn useful information about the effects of rituximab on quality of life and economic measures. The trial results will help decide the best treatment for future patients who have their vasculitis initially treated with rituximab. RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we anticipate that most will respond well. If their disease is under reasonable control after four months, further treatment with either rituximab (a single dose ever four months for two years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and azathioprine groups will then be compared. Patients will be in the trial for four years. The study has been designed by members of the European Vasculitis Study group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30 hospitals in Europe, the USA, Australia and Mexico. RITAZAREM is being funded by Arthritis Research UK, the U. S. National Institutes of Health and by Roche/Genentech.

Clinical Details

Official title: An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Time to relapse

Secondary outcome:

Remission at 24 and 48 months

Combined damage assessment score

Health-related quality of life

Cumulative GC exposure

Severe adverse event rate

Infection rates

Detailed description: Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week x 4 and glucocorticoids. Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 will be randomised to the rituximab or control remission maintenance groups. Treatment is protocolised for the entire duration of the study, until the common close date, when the final patient recruited has completed 36 months within the study or until the patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm will receive treatment until month 20, and those in the azathioprine arm until month 27.

Eligibility

Minimum age: 15 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis], according to the definitions of the Chapel Hill Consensus Conference 2. Current or historical PR3/MPO ANCA positivity by ELISA 3. Disease relapse defined by one major or three minor disease activity items on the Birmingham Vasculitis Activity Score for Wegeners (BVAS/WG), in patients that have previously achieved remission following at least 3 months of induction therapy, with a combination of glucocorticoids and an immunosuppressive agent (cyclophosphamide or methotrexate or rituximab or mycophenolate mofetil) 4. Written informed consent Exclusion Criteria: 1. Age < 15 years (age < 18 years at centres that do not treat paediatric patients) 2. Exclusions related to medication: Previous therapy with: 1. Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months 2. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months 3. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months 4. Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer) 3. Exclusions related to general health: 1. Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation 2. Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic vasculitis, 3. Any concomitant condition anticipated to likely require greater than 4 weeks per year of oral or systemic glucocorticoid use and which would preclude compliance with the glucocorticoid protocol (e. g. poorly-controlled asthma, COPD, psoriasis, or inflammatory bowel disease). 4. History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies 5. Known infection with HIV (HIV testing will not be a requirement for trial entry); a past or current history of hepatitis B virus or hepatitis C virus infection. 6. Ongoing or recent (last 12 months) evidence of active tuberculosis or known active infection (screening for tuberculosis is part of "standard of care‟ in patients with established AAV) or evidence of untreated latent tuberculosis. Screening for tuberculosis is as per local practice. 7. History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure. 8. Pregnancy or inadequate contraception in pre-menopausal women 9. Breast feeding or lactating 4. Exclusion criteria related to laboratory parameters: 1. Bone marrow suppression as evidenced by a total white count < 4 x109/l, haemoglobin < 7 gm/dl or platelet count < 100,000/μl 2. Aspartate aminotransferase or alanine aminotransferase or amylase > 2. 5 times the upper limit of normal, unless attributed to vasculitis

Locations and Contacts

David Jayne, Email: dj106@cam.ac.uk

Chiba University, Chiba-shi 263-8522, Japan; Recruiting
Shunsuke Furuta

Kitano Hospital, Kyoto 606-8501, Japan; Recruiting
Toshiko Ito-Ihara, MD, Email: itoshi@kuhp.kyoto-u.ac.jp

University of Miyazaki, Miyazaki 889-2192, Japan; Recruiting
Shouichi Fujimoto

Kyorin University school of medicine, Tokyo 192-0005, Japan; Recruiting
Yoshihiro Arimura, Email: arimuray@ks.kyorin-u.ac.jp

Teikyo University, Tokyo 173-0003, Japan; Recruiting
Shyunya Uchida, MD, Email: s-uchida@med.teikyo-u.ac.jp

Tokyo Metropolitan Geriatric, Tokyo 173-0015, Japan; Recruiting
Yoshitomo Hamano, MD, Email: hamanoyoshitomo@jcom.home.ne.jp

Karolinska University Hospital, Stockholm, Sweden; Recruiting
Annette Bruchfeld, Email: Annette.Bruchfeld@ki.se

Brighton and Sussex University Hospitals, Brighton BN2 5BE, United Kingdom; Recruiting
Sarah Lawman, MD, Email: Sarah.Lawman@bsuh.nhs.uk

Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Recruiting
Kim Mynard, Email: kim.mynard@addenbrookes.nhs.uk
David Jayne, Principal Investigator

Ipswich Hospital, Ipswich IP4 5PD, United Kingdom; Recruiting
Richard Watts, MD, Email: Richard.Watts@uea.ac.uk

James Cook University Hospital, Middlesbrough TS4 3BW, United Kingdom; Recruiting
John Main, MD, Email: John.Main@stees.nhs.uk
Caroling Wroe, MD, Email: caroline.wroe@qmc.nhs.uk

Queen's Medical Centre Campus, Nottingham University Hosp, Nottingham NG7 2UH, United Kingdom; Recruiting
Peter Lanyon, MD, Email: peter.lanyon@qmc.nhs.uk

University of Oxford, Oxford OX1 2JD, United Kingdom; Recruiting
Raashid Luqmani, MD, Email: raashid.luqmani@ndorms.ox.ac.uk

Canberra Hospital, Garran, Australian Capital Territory, Australia; Recruiting
Paul Gatenby, MD, Email: Paul.Gatenby@act.gov.au

Cedars-Sinai Medical Center, Los Angeles, California 90048, United States; Recruiting
Michael Weisman, MD, Email: Michael.Weisman@cshs.org

Boston University School of Medicine, Boston, Massachusetts 02118, United States; Recruiting
Paul Monach, MD, PHD, Email: pmonach@bu.edu

University of Michigan, Ann Arbor, Michigan 48109, United States; Recruiting
Ora Singer, MD, Email: singero@med.umich.edu

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Ulrich Specks, MD, Email: specks.ulrich@mayo.edu

Hospital for Special Surgery, New York, New York 10021, United States; Recruiting
Robert Spiera, MD, Email: spierar@hss.edu

University of North Carolina, Chapel Hill, North Carolina 27599, United States; Recruiting
Patrick Nachman, MD, Email: patrick_nachman@med.unc.edu

Cleveland Clinic, Cleveland, Ohio 44195, United States; Recruiting
Carol Langford, MD, MHS, Email: LANGFOC@ccf.org

Okayama University, Kita Ward, Okayama 700-0082, Japan; Recruiting
Hirofumai Nakajima

St. Joseph's Healthcare, Hamilton, Ontario L8N 4A6, Canada; Recruiting
Nader Khalidi, MD, Email: naderkhalidi@sympatico.ca

Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Recruiting
Simon Carette, MD, Email: simon.carette@uhn.on.ca

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Peter Merkel, MD, Email: peter.merkel@uphs.upenn.edu
Carol McAlear, MA, Email: cmcalear@upenn.edu
Peter Merkel, MD, Principal Investigator
Antoine Sreih, MD, Sub-Investigator

University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Recruiting
Larry Moreland, MD, Email: lwm5@pitt.edu

Royal Adelaide Hospital, Adelaide, South Australia, Australia; Recruiting
Chen Au Peh, MD, Email: chen.peh@adelaide.edu.au

University of Utah, Salt Lake City, Utah 84112, United States; Recruiting
Curry Koening, MD, MS, Email: curry.koening@hsc.utah.edu

Additional Information

RITAZAREM trial information with links to CRFs, protocol synposis, and other trial-related information

Related publications:

Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis--is it time to reclassify? Rheumatology (Oxford). 2011 Apr;50(4):643-5. doi: 10.1093/rheumatology/keq229. Epub 2010 Jul 20.

Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 2010 May;21(5):745-52. doi: 10.1681/ASN.2009121238. Epub 2010 Apr 15. Review.

Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003 Jan;15(1):11-6. Review.

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.

Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44.

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.

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.

Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61.

Seo P, Min YI, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, Davis JC, Ytterberg SR, St Clair EW, McCune WJ, Specks U, Allen NB, Luqmani RA, Stone JH; WGET Research Group. Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005 Jul;52(7):2168-78.

Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.

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.

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.

Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul;60(7):2156-68. doi: 10.1002/art.24637.

Starting date: April 2013
Last updated: February 13, 2015

Page last updated: August 23, 2015

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