Rituximab Vasculitis Maintenance Study (RITAZAREM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Cambridge University Hospitals NHS Foundation Trust
Sponsor:
Collaborators:
Arthritis Research UK
Roche Pharma AG
Genentech
University of Pennsylvania
Information provided by (Responsible Party):
David Jayne, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01697267
First received: August 31, 2012
Last updated: July 9, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Microscopic Polyangiitis
Wegener Granulomatosis
Biological: Rituximab
Drug: Azathioprine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis

Resource links provided by NLM:


Further study details as provided by Cambridge University Hospitals NHS Foundation Trust:

Primary Outcome Measures:
  • Time to relapse [ Time Frame: Any patients who have not relapsed at up to a maximum of 4 years will be censored. ] [ Designated as safety issue: No ]
    The primary endpoint is the time to disease relapse (either minor or major relapse) from randomisation.


Secondary Outcome Measures:
  • Remission at 24 and 48 months [ Time Frame: 24 and 48 months ] [ Designated as safety issue: No ]
    Proportion of patients who maintain remission at 24 and 48 months

  • Combined damage assessment score [ Time Frame: Assessed at months 0, 4, 12, 24, 36 ] [ Designated as safety issue: No ]
    Cumulative accrual of damage as measured by the combined damage assessment score (CDA)

  • Health-related quality of life [ Time Frame: Assessed at months 0, 4, 12, 24, 36 ] [ Designated as safety issue: No ]
    Health-related quality of life as measured using SF-36

  • Cumulative GC exposure [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Cumulative glucocorticoid (GC) exposure during the trial

  • Severe adverse event rate [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    Severe adverse event (SAE) rate

  • Infection rates [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    Infection (treated with intravenous or oral antibiotics) rates


Estimated Enrollment: 190
Study Start Date: April 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab Maintenance
Rituximab maintenance: 1g at 4, 8, 12, 16 & 20 months with standardised steroid taper
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.
Other Names:
  • Rituxan
  • MabThera
Active Comparator: Azathioprine Maintenance
Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation). Azathioprine withdrawn at month 27.
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%.

Other Name: Imuran

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

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis], according to the definitions of the Chapel Hill Consensus Conference
  • Current or historical ANCA positivity either by ELISA or immunofluorescence
  • 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)
  • Written informed consent

Exclusion Criteria:

  • Age < 15 years (age < 18 years at centres that do not treat paediatric patients)
  • Exclusions related to medication:

Previous therapy with:

a. Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months b. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months c. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months d. Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer)

  • 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01697267

Contacts
Contact: David Jayne dj106@cam.ac.uk
Contact: Michelle Lewin michelle.lewin@addenbrookes.nhs.uk

Locations
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Peter Merkel, MD    215-614-4401    peter.merkel@uphs.upenn.edu   
Contact: Carol McAlear, MA    1-781-321-4567    cmcalear@upenn.edu   
Principal Investigator: Peter Merkel, MD         
United Kingdom
Addenbrooke's Hospital Recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Michelle Lewin       michelle.lewin@addenbrookes.nhs.uk   
Principal Investigator: David Jayne         
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
Arthritis Research UK
Roche Pharma AG
Genentech
University of Pennsylvania
Investigators
Study Chair: David Jayne Cambridge University Hospitals NHS Foundation Trust
Study Chair: Peter Merkel University of Pennsylvania
  More Information

Additional Information:
Publications:

Responsible Party: David Jayne, Director, Vasculitis and Lupus Clinic, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01697267     History of Changes
Other Study ID Numbers: RITAZAREM 1.0, 2012-001102-14
Study First Received: August 31, 2012
Last Updated: July 9, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration
Austria: Agency for Health and Food Safety
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Netherlands: Dutch Health Care Inspectorate
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
Switzerland: Swissmedic
Canada: Health Canada
Mexico: Federal Commission for Protection Against Health Risks
Australia: Department of Health and Ageing Therapeutic Goods Administration
New Zealand: Medsafe

Keywords provided by Cambridge University Hospitals NHS Foundation Trust:
vasculitis
ANCA vasculitis
microscopic polyangiitis
granulomatosis
Wegener's
AAV
vasculitides

Additional relevant MeSH terms:
Wegener Granulomatosis
Vasculitis
Systemic Vasculitis
Microscopic Polyangiitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Autoimmune Diseases
Immune System Diseases
Azathioprine
Rituximab
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 29, 2014