Rituximab Vasculitis Maintenance Study

NCT01697267 | Completed Phase 3 Results DMC

• 2 other identifiers: RITAZAREM2012-001102-14
• Study Type: interventional
• Target: 188
• Locations: 10 countries
• Sites: 38

Brief 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.

Conditions

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

Keywords

vasculitis; ANCA vasculitis; microscopic polyangiitis; granulomatosis; Wegener's; AAV; vasculitides

Outcome Measures

Primary Outcomes (1)

• Relapse-free Survival

  The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).

  Any patients who have not relapsed at up to a maximum of 4 years will be censored.

Secondary Outcomes (15)

• Number of Participants in Remission at 24 and 48 Months

  24 and 48 months

• Combined Damage Assessment Score (Disease Related Damage Assessment)

  data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.

• Cumulative GC Exposure

  Up to 48 months

• Severe Adverse Event Rate

  Up to 48 months

• Infection Rates

  Up to 4 years

Study Arms (2)

Rituximab Maintenance

EXPERIMENTAL

Rituximab maintenance: 1g at 4, 8, 12, 16 \& 20 months with standardised steroid taper

Biological: Rituximab

Azathioprine Maintenance

ACTIVE COMPARATOR

Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.

Drug: Azathioprine

Interventions

Rituximab BIOLOGICAL

Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.

Also known as: Rituxan, MabThera

Rituximab Maintenance

Azathioprine DRUG

Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27. The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily. If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.

Also known as: Imuran

Azathioprine Maintenance

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of AAV \[granulomatosis with polyangiitis or microscopic polyangiitis\], according to the definitions of the Chapel Hill Consensus Conference
• Current or historical PR3/MPO ANCA positivity by ELISA
• 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)
• Written informed consent

You may not qualify if:

• Age \< 15 years (age \< 18 years at centres that do not treat paediatric patients)
• Previous therapy with:
• Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months
• Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months
• IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months
• Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer)
• Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation
• Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic vasculitis,
• 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).
• History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies
• 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.
• 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.
• 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.
• Pregnancy or inadequate contraception in pre-menopausal women
• Breast feeding or lactating

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• Arthritis Research UK: collaborator
• Roche Pharma AG: collaborator
• Genentech, Inc.: collaborator
• University of Pennsylvania: collaborator

Study Sites (38)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Hospital for Special Surgery

New York, New York, 10021, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15260, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Canberra Hospital

Garran, Australian Capital Territory, Australia

Location

Royal Brisbane & Women's Hospital

Herston, Queensland, 4029, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Location

St. Joseph's Healthcare

Hamilton, Ontario, L8N 4A6, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, M5T 3L9, Canada

Location

General Faculty Hospital

Prague, Czechia

Location

Cork University Hospital

Cork, Ireland

Location

University Hospital of Parma

Parma, 43100, Italy

Location

Okayama University

Kita-ku, Okayama-ken, 700-0082, Japan

Location

Chiba University

Chiba, 263-8522, Japan

Location

Kitano Hospital

Kyoto, 606-8501, Japan

Location

University of Miyazaki

Miyazaki, 889-2192, Japan

Location

Teikyo University

Tokyo, 173-0003, Japan

Location

Tokyo Metropolitan Geriatric

Tokyo, 173-0015, Japan

Location

Kyorin University school of medicine

Tokyo, 192-0005, Japan

Location

Auckland City Hospital

Grafton, Auckland, 1023, New Zealand

Location

North Shore Hospital

Westlake, Auckland, New Zealand

Location

Karolinska University Hospital

Stockholm, Sweden

Location

Leicester General Hospital

Leicester, Leicestershire, LE5 4PW, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, B15 2WB, United Kingdom

Location

Brighton and Sussex University Hospitals

Brighton, BN2 5BE, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Russells Hall Hospital

Dudley, DY1 2HQ, United Kingdom

Location

Ipswich Hospital

Ipswich, IP4 5PD, United Kingdom

Location

Chapel Allerton Hospital

Leeds, LS7 4SA, United Kingdom

Location

Imperial College

London, W12 0NN, United Kingdom

Location

James Cook University Hospital

Middlesbrough, TS4 3BW, United Kingdom

Location

Queen's Medical Centre Campus, Nottingham University Hosp

Nottingham, NG7 2UH, United Kingdom

Location

University of Oxford

Oxford, OX1 2JD, United Kingdom

Location

Related Publications (15)

• 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. No abstract available.

  PMID: 20647295 BACKGROUND

• 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.

  PMID: 20395376 BACKGROUND

• Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003 Jan;15(1):11-6. doi: 10.1097/00002281-200301000-00003.

  PMID: 12496504 BACKGROUND

• 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

• Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene 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. doi: 10.1056/NEJMoa020286.

  PMID: 12840090 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

• 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. doi: 10.1056/NEJMoa041884.

  PMID: 15673801 BACKGROUND

• 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. doi: 10.1002/art.21117.

  PMID: 15986348 BACKGROUND

• 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.

  PMID: 7506951 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

• 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, 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.

  PMID: 19565480 BACKGROUND

• Smith RM, Jones RB, Specks U, Bond S, Nodale M, Al-Jayyousi R, Andrews J, Bruchfeld A, Camilleri B, Carette S, Cheung CK, Derebail V, Doulton T, Ferraro A, Forbess L, Fujimoto S, Furuta S, Gewurz-Singer O, Harper L, Ito-Ihara T, Khalidi N, Klocke R, Koening C, Komagata Y, Langford C, Lanyon P, Luqmani R, McAlear C, Moreland LW, Mynard K, Nachman P, Pagnoux C, Peh CA, Pusey C, Ranganathan D, Rhee RL, Spiera R, Sreih AG, Tesar V, Walters G, Wroe C, Jayne D, Merkel PA; RITAZAREM co-investigators. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial. Ann Rheum Dis. 2023 Jul;82(7):937-944. doi: 10.1136/ard-2022-223559. Epub 2023 Mar 23.

  PMID: 36958796 DERIVED

• Gopaluni S, Smith RM, Lewin M, McAlear CA, Mynard K, Jones RB, Specks U, Merkel PA, Jayne DR; RITAZAREM Investigators. Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trials. 2017 Mar 7;18(1):112. doi: 10.1186/s13063-017-1857-z.

  PMID: 28270229 DERIVED

MeSH Terms

Conditions

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

Interventions

Rituximab; Azathioprine

Condition Hierarchy (Ancestors)

Systemic 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; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Prof David Jayne
• Organization: Cambridge University Hospitals NHS Foundation Trust

dj106@cam.ac.uk

01223 748062

Study Officials

• David Jayne

  Cambridge University Hospitals NHS Foundation Trust

  STUDY CHAIR

• Peter Merkel

  University of Pennsylvania

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Vasculitis and Lupus Clinic

Study Record Dates

• First Submitted: August 31, 2012
• First Posted: October 2, 2012
• Study Start: April 1, 2013
• Primary Completion: November 22, 2018
• Study Completion: November 21, 2019
• Last Updated: March 18, 2022
• Results First Posted: March 18, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

NZ (2); CZ (1); JP (7); AU (3); IE (1); IT (1); US (9); GB (11); CA (2); SE (1)