Rituximab Vasculitis Maintenance Study

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Brief Title

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

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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Time to relapse

Secondary Outcome

 Remission at 24 and 48 months

Condition

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Intervention

Rituximab

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

188

Start Date

April 2013

Completion Date

November 21, 2019

Primary Completion Date

November 22, 2018

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
      

Gender

All

Ages

15 Years - N/A

Accepts Healthy Volunteers

No

Contacts

David Jayne, , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT01697267

Organization ID

RITAZAREM

Secondary IDs

2012-001102-14

Responsible Party

Principal Investigator

Study Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

 Arthritis Research UK

Study Sponsor

David Jayne, Study Chair, Cambridge University Hospitals NHS Foundation Trust


Verification Date

January 2021