Rituximab Vasculitis Maintenance Study

Cambridge University Hospitals NHS Foundation Trust188 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Interventions

RituximabBIOLOGICAL

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.

AzathioprineDRUG

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%.

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

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 (38)

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Hospital for Special Surgery

New York, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Outcomes

Primary Outcomes

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%).

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

Secondary Outcomes

Number of Participants in Remission at 24 and 48 Months

Proportion of patients who maintain remission at 24 and 48 months

Time frame: 24 and 48 months

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).

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

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).

Time frame: Up to 48 months

Severe Adverse Event Rate

Severe adverse event (SAE) rate

Time frame: Up to 48 months

Infection Rates

Infection (treated with intravenous or oral antibiotics) rates

Time frame: Up to 4 years