Rituximab Vasculitis Maintenance Study

Microscopic Polyangiitis Clinical Trial

— RITAZAREM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01697267
• Other study ID #: RITAZAREM
• Secondary ID: 2012-001102-14
• Status: Completed
• Phase: Phase 3
• Start date: April 2013
• Est. completion date: November 21, 2019

Study information

• Verified date: February 2022
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 188
• Est. completion date: November 21, 2019
• Est. primary completion date: November 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Granulomatosis with Polyangiitis
• Microscopic Polyangiitis
• Systemic Vasculitis
• Vasculitis
• Wegener Granulomatosis

Intervention

Biological:
• 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.

Drug:
• 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%.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Canberra Hospital	Garran	Australian Capital Territory
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Canada	St. Joseph's Healthcare	Hamilton	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Czechia	General Faculty Hospital	Prague
Ireland	Cork University Hospital	Cork
Italy	University Hospital of Parma	Parma
Japan	Chiba University	Chiba-shi
Japan	Okayama University	Kita-ku	Okayama
Japan	Kitano Hospital	Kyoto
Japan	University of Miyazaki	Miyazaki
Japan	Kyorin University school of medicine	Tokyo
Japan	Teikyo University	Tokyo
Japan	Tokyo Metropolitan Geriatric	Tokyo
New Zealand	Auckland City Hospital	Grafton	Auckland
New Zealand	North Shore Hospital	Westlake	Auckland
Sweden	Karolinska University Hospital	Stockholm
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Brighton and Sussex University Hospitals	Brighton
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Russells Hall Hospital	Dudley
United Kingdom	Ipswich Hospital	Ipswich
United Kingdom	Chapel Allerton Hospital	Leeds
United Kingdom	Leicester General Hospital	Leicester	Leicestershire
United Kingdom	Imperial College	London
United Kingdom	James Cook University Hospital	Middlesbrough
United Kingdom	Queen's Medical Centre Campus, Nottingham University Hosp	Nottingham
United Kingdom	University of Oxford	Oxford
United States	University of Michigan	Ann Arbor	Michigan
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Hospital for Special Surgery	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah

Sponsors (5)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust	Arthritis Research UK, Genentech, Inc., Roche Pharma AG, University of Pennsylvania

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czechia,  Ireland,  Italy,  Japan,  New Zealand,  Sweden,  United Kingdom, 

References & Publications (13)

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. — View Citation

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. — View 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. — View Citation

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. — View Citation

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. — View 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. — View 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. — View Citation

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. — View 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. — View 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. — View Citation

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

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 a-level of 5%).	Any patients who have not relapsed at up to a maximum of 4 years will be censored.
Secondary	Number of Participants in Remission at 24 and 48 Months	Proportion of patients who maintain remission at 24 and 48 months	24 and 48 months
Secondary	Combined Damage Assessment Score (Disease Related Damage Assessment)	Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64).	data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.
Secondary	Cumulative GC Exposure	Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36).	Up to 48 months
Secondary	Severe Adverse Event Rate	Severe adverse event (SAE) rate	Up to 48 months
Secondary	Infection Rates	Infection (treated with intravenous or oral antibiotics) rates	Up to 4 years
Secondary	Health-related Quality of Life Using the SF-36 Physical Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	4 months
Secondary	Health-related Quality of Life Using the SF-36 Mental Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	4 months
Secondary	Health-related Quality of Life Using the SF-36 Physical Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	12 months
Secondary	Health-related Quality of Life Using the SF-36 Mental Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	12 months
Secondary	Health-related Quality of Life Using the SF-36 Physical Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	24 months
Secondary	Health-related Quality of Life Using the SF-36 Mental Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	24 months
Secondary	Health-related Quality of Life Using the SF-36 Physical Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	36 months
Secondary	Health-related Quality of Life Using the SF-36 Mental Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	36 months
Secondary	Health-related Quality of Life Using the SF-36 Physical Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	48 months
Secondary	Health-related Quality of Life Using the SF-36 Mental Composite	The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	48 months