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Rituximab Vasculitis Maintenance Study (RITAZAREM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01697267
Recruitment Status : Completed
First Posted : October 2, 2012
Results First Posted : March 18, 2022
Last Update Posted : March 18, 2022
Sponsor:
Collaborators:
Arthritis Research UK
Roche Pharma AG
Genentech, Inc.
University of Pennsylvania
Information provided by (Responsible Party):
David Jayne, Cambridge University Hospitals NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE August 31, 2012
First Posted Date  ICMJE October 2, 2012
Results First Submitted Date  ICMJE March 17, 2021
Results First Posted Date  ICMJE March 18, 2022
Last Update Posted Date March 18, 2022
Actual Study Start Date  ICMJE April 2013
Actual Primary Completion Date November 22, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2022)
Relapse-free Survival [ Time Frame: Any patients who have not relapsed at up to a maximum of 4 years will be censored. ]
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%).
Original Primary Outcome Measures  ICMJE
 (submitted: October 1, 2012)
Time to relapse [ Time Frame: Any patients who have not relapsed at up to a maximum of 4 years will be censored. ]
The primary endpoint is the time to disease relapse (either minor or major relapse) from randomisation.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2022)
  • Number of Participants in Remission at 24 and 48 Months [ Time Frame: 24 and 48 months ]
    Proportion of patients who maintain remission at 24 and 48 months
  • Combined Damage Assessment Score (Disease Related Damage Assessment) [ Time Frame: data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48. ]
    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).
  • Cumulative GC Exposure [ Time Frame: Up to 48 months ]
    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).
  • Severe Adverse Event Rate [ Time Frame: Up to 48 months ]
    Severe adverse event (SAE) rate
  • Infection Rates [ Time Frame: Up to 4 years ]
    Infection (treated with intravenous or oral antibiotics) rates
  • Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 4 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 4 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 12 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 12 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 24 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 24 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 36 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 36 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 48 months ]
    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.
  • Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 48 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2012)
  • Remission at 24 and 48 months [ Time Frame: 24 and 48 months ]
    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 ]
    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 ]
    Health-related quality of life as measured using SF-36
  • Cumulative GC exposure [ Time Frame: Up to 4 years ]
    Cumulative glucocorticoid (GC) exposure during the trial
  • Severe adverse event rate [ Time Frame: Up to 4 years ]
    Severe adverse event (SAE) rate
  • Infection rates [ Time Frame: Up to 4 years ]
    Infection (treated with intravenous or oral antibiotics) rates
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab Vasculitis Maintenance Study
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
  • Microscopic Polyangiitis
  • Wegener Granulomatosis
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: Rituximab Maintenance
    Rituximab maintenance: 1g at 4, 8, 12, 16 & 20 months with standardised steroid taper
    Intervention: Biological: Rituximab
  • 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.
    Intervention: Drug: Azathioprine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 27, 2020)
188
Original Estimated Enrollment  ICMJE
 (submitted: October 1, 2012)
190
Actual Study Completion Date  ICMJE November 21, 2019
Actual Primary Completion Date November 22, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Czechia,   Ireland,   Italy,   Japan,   New Zealand,   Sweden,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01697267
Other Study ID Numbers  ICMJE RITAZAREM
2012-001102-14 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party David Jayne, Cambridge University Hospitals NHS Foundation Trust
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Cambridge University Hospitals NHS Foundation Trust
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Arthritis Research UK
  • Roche Pharma AG
  • Genentech, Inc.
  • University of Pennsylvania
Investigators  ICMJE
Study Chair: David Jayne Cambridge University Hospitals NHS Foundation Trust
Study Chair: Peter Merkel University of Pennsylvania
PRS Account Cambridge University Hospitals NHS Foundation Trust
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP