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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01697267




Registration number
NCT01697267
Ethics application status
Date submitted
31/08/2012
Date registered
2/10/2012
Date last updated
28/02/2020

Titles & IDs
Public title
Rituximab Vasculitis Maintenance Study
Scientific title
An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis
Secondary ID [1] 0 0
2012-001102-14
Secondary ID [2] 0 0
RITAZAREM
Universal Trial Number (UTN)
Trial acronym
RITAZAREM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis 0 0
Microscopic Polyangiitis 0 0
Wegener Granulomatosis 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system
Inflammatory and Immune System 0 0 0 0
Autoimmune diseases
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Rituximab
Treatment: Drugs - Azathioprine

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

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 Azathioprine withdrawn at month 27.


Other interventions: Rituximab
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.

Treatment: Drugs: Azathioprine
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 The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.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%.

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Time to relapse - The primary endpoint is the time to disease relapse (either minor or major relapse) from randomisation.
Timepoint [1] 0 0
Any patients who have not relapsed at up to a maximum of 4 years will be censored.
Secondary outcome [1] 0 0
Remission at 24 and 48 months - Proportion of patients who maintain remission at 24 and 48 months
Timepoint [1] 0 0
24 and 48 months
Secondary outcome [2] 0 0
Combined damage assessment score - Cumulative accrual of damage as measured by the combined damage assessment score (CDA)
Timepoint [2] 0 0
Assessed at months 0, 4, 12, 24, 36
Secondary outcome [3] 0 0
Health-related quality of life - Health-related quality of life as measured using SF-36
Timepoint [3] 0 0
Assessed at months 0, 4, 12, 24, 36
Secondary outcome [4] 0 0
Cumulative GC exposure - Cumulative glucocorticoid (GC) exposure during the trial
Timepoint [4] 0 0
Up to 4 years
Secondary outcome [5] 0 0
Severe adverse event rate - Severe adverse event (SAE) rate
Timepoint [5] 0 0
Up to 4 years
Secondary outcome [6] 0 0
Infection rates - Infection (treated with intravenous or oral antibiotics) rates
Timepoint [6] 0 0
Up to 4 years

Eligibility
Key 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
Minimum age
15 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,QLD,SA
Recruitment hospital [1] 0 0
Canberra Hospital - Garran
Recruitment hospital [2] 0 0
Royal Brisbane & Women's Hospital - Herston
Recruitment hospital [3] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 0 0
- Garran
Recruitment postcode(s) [2] 0 0
4029 - Herston
Recruitment postcode(s) [3] 0 0
- Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Michigan
Country [3] 0 0
United States of America
State/province [3] 0 0
Minnesota
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Utah
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
Czechia
State/province [10] 0 0
Prague
Country [11] 0 0
Ireland
State/province [11] 0 0
Cork
Country [12] 0 0
Italy
State/province [12] 0 0
Parma
Country [13] 0 0
Japan
State/province [13] 0 0
Okayama
Country [14] 0 0
Japan
State/province [14] 0 0
Chiba-shi
Country [15] 0 0
Japan
State/province [15] 0 0
Kyoto
Country [16] 0 0
Japan
State/province [16] 0 0
Miyazaki
Country [17] 0 0
Japan
State/province [17] 0 0
Tokyo
Country [18] 0 0
New Zealand
State/province [18] 0 0
Auckland
Country [19] 0 0
Sweden
State/province [19] 0 0
Stockholm
Country [20] 0 0
United Kingdom
State/province [20] 0 0
Leicestershire
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Birmingham
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Brighton
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Cambridge
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Dudley
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Ipswich
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Leeds
Country [27] 0 0
United Kingdom
State/province [27] 0 0
London
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Middlesbrough
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Nottingham
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Other
Name
Cambridge University Hospitals NHS Foundation Trust
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Arthritis Research UK
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Roche Pharma AG
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Genentech, Inc.
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
University of Pennsylvania
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01697267
Trial related presentations / 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.
Public notes

Contacts
Principal investigator
Name 0 0
David Jayne
Address 0 0
Cambridge University Hospitals NHS Foundation Trust
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications