Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing (MAINTANCAVAS)
|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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02749292|
Recruitment Status : Recruiting
First Posted : April 22, 2016
Last Update Posted : August 21, 2018
|Condition or disease||Intervention/treatment||Phase|
|Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis||Drug: Rituximab||Phase 4|
Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease characterized by small vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO). Immunosuppressive therapy can result in remission; however, many patients relapse, which results in additional injury.
Rituximab, a humanized murine monoclonal antibody directed against CD20 located on the surface of B-lymphocytes (B cells), is effective in depleting B cells. The RAVE and RITUXVAS trials have shown efficacy of rituximab with steroids for induction of remission in ANCA vasculitis, similar to cyclophosphamide and steroids. Rituximab is now FDA-approved for induction of remission therapy in ANCA vasculitis. The utility of anti-B-cell therapy for early induction of remission in ANCA vasculitis is not surprising given that ANCA are pathogenic in vitro and in vivo. It is clear that remission in many patients is not sustained with a single induction course of rituximab, and relapses often occur after B cell re-population suggesting that scheduled, serial dosing of rituximab could result in sustained remissions.
Despite yielding promising outcomes, rituximab is also associated with a number of adverse events including infectious complications and late onset of neutropenia5, 15. Furthermore, the complications of continuous B cell depletion for extended durations are unknown. One of the major goals in the field is to utilize prolonged B cell depletion only in the subpopulation of patients where the risk of disease relapse outweighs the risk of treatment-related adverse events.
A rise in ANCA titers and reconstitution of B cells are promising biomarkers of impending disease relapse following treatment with rituximab4-6
A prospective and longitudinal clinical trial is needed to determine the ideal treatment strategy for long-term maintenance of remission. We propose to compare intermittent rituximab dosing based on B cell return and a serologic ANCA flare
The study design is an open-label, single center, randomized and two-arm controlled trial to evaluate the optimal maintenance of remission strategy that provides the best relapse-free survival in patients with ANCA vasculitis as determined by relapse-free remission at 18, 24 and 36 months from enrollment. The investigators are looking to enroll and randomize 200 subjects with ANCA vasculitis on rituximab-induced continuous B cell depletion for a minimum of two years to one of two arms as follows:
- Intermittent B cell depletion with rituximab re-dosing upon B cell return: Subjects will not receive their regularly-scheduled every-six-month dose of rituximab and will instead receive rituximab 1000 mg IV x 2 doses (spaced 2-3 weeks apart) once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months.
- Hold continuous dosing with rituximab with re-dosing upon a significant ANCA titer increase: For MPO, a significant increase will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects will not receive regularly scheduled every six-month doses of rituximab and will instead be monitored every three months. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing Based on B-cell Reconstitution vs a Serologic ANCA Flare|
|Study Start Date :||June 2016|
|Estimated Primary Completion Date :||October 2020|
|Estimated Study Completion Date :||October 2020|
Active Comparator: B cell reconstitution
Subjects will no longer receive regularly-scheduled every six-month doses of rituximab (1000mg IV) and will instead be monitored every three months for B cell return. Once peripheral B cells rise to ≥ 10cells/mm3 they will receive rituximab 1000 mg IV x 2 (doses spaced approx. 2-3 weeks apart). Subsequent dosing will be again based on B cell return (≥ 10 B cells/mm3), with patients seen in clinic and B cells monitored every 3 months.
re-dosing dependent on interventional arm parameter.
Other Name: Rituxan
Active Comparator: Serologic ANCA flare
Subjects will not receive regularly-scheduled every six-month doses of rituximab (1000mg IV) and will instead be monitored every three months in clinic. Re-dosing will occur once the subject's ANCA titer has risen above the predetermined treatment value (MPO treatment value defined as a 5-fold rise from baseline and a level greater than 4 times the cutoff value for the assay; PR3 treatment value defined as a 4-fold rise from baseline and a level greater than 2-fold above the cutoff for the assay). Subjects who meet this criteria will then be re-dosed with rituximab 1000 mg IV x2 (spaced 2-3 weeks apart). If the ANCA titer remains 2-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO), subjects will then receive rituximab 1000mg IV every 6 months x 2 doses and a new ANCA titer baseline will be established. The cycle will then re-start.
re-dosing dependent on interventional arm parameter.
Other Name: Rituxan
- Number of disease relapses as defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 [ Time Frame: 3 years ]
- Number of serious adverse events [ Time Frame: 3 years ]
- Composite of disease relapse (defined a BVAS/WG ≥ 2) and serious adverse events [ Time Frame: 3 years ]
- Hypogammaglobulinemia defined as an IgG < 400 mg/dL [ Time Frame: 3 years ]
- Patient Survival [ Time Frame: 3 years ]
- Health-related quality of life as assessed by the Short Form Health Survey (SF-36) score [ Time Frame: 3 years ]
- Rituximab utilization measured in grams/patient [ Time Frame: 3 years ]
- Organ damage as assessed by the Vasculitis Damage Index (VDI) [ Time Frame: 3 years ]
- Number of major relapses defined as a BVAS/WG ≥ 3 [ Time Frame: 3 years ]
- Number of infections defined as receiving oral or IV antibiotics [ Time Frame: 3 years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02749292
|Contact: John L Niles, MDfirstname.lastname@example.org|
|Contact: Karen Laliberte, RN, MSNemail@example.com|
|United States, Massachusetts|
|Massachusetts General Hospital||Recruiting|
|Boston, Massachusetts, United States, 02114|
|Contact: Karen Laliberte, MSN 617-726-4132 firstname.lastname@example.org|
|Contact: Andrew Murphy, MBA 617-726-4132 email@example.com|
|Principal Investigator:||John L Niles, MD||Massachusetts General Hospital|