Clinical trial NCT01697267: Rituximab Vasculitis Maintenance Study
Official title: An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Microscopic Polyangiitis
Wegener Granulomatosis
Keywords: vasculitis
ANCA vasculitis
microscopic polyangiitis
granulomatosis
Wegener's
AAV
vasculitides
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Arthritis Research UK
name: Roche Pharma AG
name: Genentech, Inc.
name: University of Pennsylvania
First posted: 2012-10-02
Enrollment: 188
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Relapse-free Survival
timeFrame: Any patients who have not relapsed at up to a maximum of 4 years will be censored.
Secondary outcomes:
measure: Number of Participants in Remission at 24 and 48 Months
timeFrame: 24 and 48 months
measure: Combined Damage Assessment Score (Disease Related Damage Assessment)
timeFrame: data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.
measure: Cumulative GC Exposure
timeFrame: Up to 48 months
measure: Severe Adverse Event Rate
timeFrame: Up to 48 months
measure: Infection Rates
timeFrame: Up to 4 years
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 4 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 4 months
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 12 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 12 months
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 24 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 24 months
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 36 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 36 months
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 48 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 48 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Prague
country: Czechia
facility: General Faculty Hospital
city: Cork
country: Ireland
facility: Cork University Hospital
city: Parma
country: Italy
facility: University Hospital of Parma
city: Kita-ku
country: Japan
facility: Okayama University
state: Okayama
city: Chiba-shi
country: Japan
facility: Chiba University
city: Kyoto
country: Japan
facility: Kitano Hospital
city: Miyazaki
country: Japan
facility: University of Miyazaki
city: Tokyo
country: Japan
facility: Teikyo University
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Geriatric
city: Tokyo
country: Japan
facility: Kyorin University school of medicine
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Westlake
country: New Zealand
facility: North Shore Hospital
state: Auckland
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
state: Leicestershire
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Leeds
country: United Kingdom
facility: Chapel Allerton Hospital
city: London
country: United Kingdom
facility: Imperial College
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre Campus, Nottingham University Hosp
city: Oxford
country: United Kingdom
facility: University of Oxford
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: David Jayne
role: STUDY_CHAIR
affiliation: University of Pennsylvania
name: Peter Merkel
role: STUDY_CHAIR
References:
citation: 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.
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citation: Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003 Jan;15(1):11-6. doi: 10.1097/00002281-200301000-00003.
citation: 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.
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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. doi: 10.1002/art.21142.
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citation: 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.
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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.
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.
citation: 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.
citation: 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.