MAINTANCAVAS: Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT02749292

Collaborator

(none)

200

Enrollment

Location

Arms

Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis	Drug: Rituximab	Phase 4

Detailed Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2016

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Rituximab re-dosing dependent on interventional arm parameter. Other Names: 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.	Drug: Rituximab re-dosing dependent on interventional arm parameter. Other Names: Rituxan

Arm

Intervention/Treatment

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.

Drug: Rituximab

re-dosing dependent on interventional arm parameter.

Other Names:

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.

Drug: Rituximab

re-dosing dependent on interventional arm parameter.

Other Names:

Rituxan

Outcome Measures

Primary Outcome Measures

Number of disease relapses as defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 [3 years]
active disease relapse

Secondary Outcome Measures

Number of serious adverse events [3 years]
adverse events as defined
Composite of disease relapse (defined a BVAS/WG ≥ 2) and serious adverse events [3 years]
disease relapse combined with SAE
Hypogammaglobulinemia defined as an IgG < 400 mg/dL [3 years]
IgG <400
Patient Survival [3 years]
mortality
Health-related quality of life as assessed by the Short Form Health Survey (SF-36) score [3 years]
quality of life
Rituximab utilization measured in grams/patient [3 years]
Rituxan dose
Organ damage as assessed by the Vasculitis Damage Index (VDI) [3 years]
organ damage
Number of major relapses defined as a BVAS/WG ≥ 3 [3 years]
major disease relapse
Number of infections defined as receiving oral or IV antibiotics [3 years]
infections requiring antibiotic treatment of any kind

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 82 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 ≥ 30 cc/min/1.73m2
Age: 18-82 years old
Treated with rituximab-induced continuous B cell depletion and in remission (defined by a modified BVAS-WG=0 AND a prednisone dose of ≤ 7.5 mg) for at least 24 months.
CD20 (B cells) undetectable at time of enrollment/randomization
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 < 250 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