Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing

Study Overview
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Brief Summary
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The purpose of this study is to determine the best management strategy to maintain remission in patients with ANCA vasculitis who have been treated with rituximab induced B cell depletion for at least two years. This study will compare intermittent B Cell depletion upon B cell return or intermittent B cell depletion upon serologic relapse.

Detailed Description
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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 1 dose (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. Patients will continue to be dosed with rituximab each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. 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 seen in clinic to have their ANCA titer 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.

Official Title
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Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing Based on B-cell Reconstitution vs a Serologic ANCA Flare

Conditions
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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must be able and willing to give written informed consent and comply with the requirements of the study protocol. Diagnosis: ANCA vasculitis as defined by a positive MPO- and/or PR3-ANCA test together with clinical features characteristic of ANCA-positive diseases as detailed in the 2012 Chapel Hill Consensus Conference Definitions(18). eGFR ≥ 73 cc/min/1.73m2 Age: 18-82 years old Treated with rituximab-induced continuous B cell depletion at regularly scheduled interval with a goal of undetectable B cells for at least 24 months In sustained remission (defined by a modified BVAS-WG=0 AND a prednisone dose of ≤ 7.5 mg) for at least 12 months. Undetectable (<10mm3) B cells (quantified by CD20+ number) on day 0 Urine Hcg negative for women of child bearing potential and not planning to become pregnant for at least 12 months from enrollment and at least 12 months after any study related rituximab dose Judged to be otherwise healthy by the Investigator, based on medical history and physical examination (no known active disease process for which life expectancy is less than 36 months) Exclusion Criteria: Secondary Disease: disease suspected to be induced by levamisole-adulterated cocaine All transplanted patients Treatment: additional immunosuppressive agents other than rituximab and/or total daily prednisone dose ≥ 7.5 milligrams Hypogammaglobulinemia: IgG level < 300 mg/dL Terminal cancer or other primary illness with life expectancy of less than 36 months Active anti-GBM disease and other known autoimmune disease for which the need for additional immunosuppression is likely Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: B cell reconstitution<br>Subjects will not receive their regularly-scheduled every-six-month dose of rituximab and will instead receive rituximab 1000 mg IV x 1 dose once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months. Patients will continue to be dosed with rituximab each time the B cell count rises to 10 cells/mm3. In the unique scenario that the B cells are detectable, but less than the threshold of 10 cells/mm3, subjects will be asked to return in 6 weeks for repeat B cell testing. | Drug: Rituximab<br>* re-dosing dependent on interventional arm parameter.<br>* Other names: Rituxan;|
| Active Comparator: Serologic ANCA flare<br>Subjects will not receive regularly scheduled every six-month doses of rituximab (1000mg IV) and will instead be seen in clinic for ANCA titer monitoring every 3 months. Re-dosing will occur upon a significant ANCA titer increase. For MPO, a significant rise 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 who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, spaced  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. | Drug: Rituximab<br>* re-dosing dependent on interventional arm parameter.<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Disease Relapse(s) as Defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 | Relapses recording period was from 6/1/2016 to 12/31/2021. The outcome was reported as the number of participants with disease relapse who had either positive ANCA titers specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Affected by Serious Adverse Events | Number of patients with serious adverse events (SAEs), including all episodes of late onset neutropenia (LON). SAE are defined in the Serious adverse event section. Serious adverse events were reported over the entire study period (5.5 years) | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 
| Composite of Disease Relapse (Defined a BVAS/WG ≥ 2) and Serious Adverse Events | Number of disease relapse added with the number of SAE in each group | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 
| Number of Patients With Hypogammaglobulinemia | Hypogammaglobulinemia defined as an IgG < 250mg/dL | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 
| Patient Survival | number of deaths throughout the study. | 5.5 years | 
| Health-related Quality of Life as Assessed by the Short Form Health Survey (SF-36) Scores | The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status and is commonly used in health economics as a variable in the quality-adjusted life year calculation to determine the cost-effectiveness of a health treatment. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. | Assessed throughout the study period, every 6 months unless such time point was not reached or was missed by the patient. Median follow-up period is of 4.1 years (IQR, 2.5 - 5.0) | 
| Mean Number of Rituximab Infusions Per Subject | The rituximab utilization was measured in how many times a subject received Rituximab throughout the study which was then averaged for all subjects in each treatment arm, including those who did not receive any infusion. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 
| Organ Damage as Assessed by the Vasculitis Damage Index (VDI). | The Vasculitis Damage Index (VDI) is a validated formal assessment tool in ANCA-associated vasculitis clinical trials. The VDI distinguishes vasculitis-induced chronic damage from active inflammation or persistent disease. Each item represents a disease manifestation and is given a score (of 1) if present for at least 3 months. Neither the cause of damage (vasculitis vs treatment) nor an ongoing activity are taken into consideration. The VDI includes 64 items categorized into 11 groups (by organ system) and the scored items are summed to give a total score ranging from 0 to 64. A higher score means more accrued damage. | 3 years starting at inclusion | 
| Number of Major Relapses Defined as a BVAS/WG ≥ 3 | The Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG ) is a form with 34 predefined items grouped into 9 organ systems. The items are clinical features observed in patients with active ANCA vasculitis. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. The total BVAS/WG score is the weighted sum of individual manifestations that are present and believed to be due to active ANCA vasculitis. Higher scores reflect more active disease. BVAS/WG scores range from 0 to 64. | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 
| Number of Infections | Number of infections mild and severe, whether they were treated or not with antibiotics | Median follow-up period of 4.1 years (IQR, 2.5 - 5.0) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rituximab, maintenance, remission