Tailoring Maintenance Therapy to Cluster of Differentiation 5 Positive (CD5+) Regulatory B Cell Recovery in ANCA Vasculitis

Study Overview
=================
Brief Summary
-----------------
ANCA vasculitis is a pauci-immune systemic small vessel vasculitis. The anti-neutrophilic cytoplasmic antibodies (ANCA) are pathogenic and cause disease by activating neutrophils which damage blood vessels. CD means cluster of differentiation . CD5 is a type I transmembrane protein found on T cells, thymocytes, and some B cells. CD20 is a type III transmembrane protein found on B cells. The investigators previously detected an association between recovery of Interleukin 10 (IL-10)-secreting CD20+ and CD5+ regulatory B cells after immunotherapy (with rituximab and corticosteroids) and decreased risk of subsequent relapse in patients with ANCA-vasculitis. The investigators hypothesize that patients with complete reconstitution of a functional regulatory B cell repertoire after induction therapy are at low risk of relapse and may be monitored conservatively without further immunotherapy. The investigators will test this hypothesis through a proof of concept randomized controlled study. Patients with normalization of CD5+ regulatory B cells will be randomized to maintenance therapy with rituximab vs. close observation without immunosuppression. Patients whose peripheral CD5+ regulatory B cells remain low after induction therapy (who are at higher risk of relapse), will receive maintenance immunosuppression with rituximab. Patients needing or randomized to maintenance therapy who are unable to receive rituximab will receive azathioprine or mycophenolate mofetil, two standard alternative medications for maintenance immunosuppression.

Detailed Description
-----------------
The goal of this study is to test the hypothesis that, in ANCA vasculitis, use of CD5+ B cells at the time of B cell reconstitution in the peripheral blood can be used to stratify patients between those with low % CD5+ B cells at greater risk of relapse who would need maintenance immunosuppression and those with normalized CD5+ B cells who would be at lower risk and relapse, and therefore may not need maintenance immunosuppression. The latter group will be randomized to either maintenance immunosuppression vs close clinical observation without maintenance immunosuppression. This study is not designed to evaluate the efficacy of new therapies in ANCA vasculitis. The treatment regimen used in the proposed study are routinely used in the treatment of patients with ANCA vasculitis and considered standard-of-care.

Official Title
-----------------
Tailoring Maintenance Therapy to CD5+ Regulatory B Cell Recovery in ANCA Vasculitis

Conditions
-----------------
ANCA Associated Vasculitis

Intervention / Treatment
-----------------
* Device: ENUMERATION OF CD5+ B Cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients 18-85 years old. ANCA Glomerulonephritis (GN) or vasculitis per Chapel Hill Consensus Criteria, with documented current or previously positive Myeloperoxidase (MPO)- or Proteinase 3 (PR3)-ANCA by ELISA test. Patients with biopsy-proven, pauci-immune crescentic glomerulonephritis are eligible if they have a positive ANCA test by immunofluorescent microscopy (IIFM). Patients must be in complete remission for at least 1 month and after AT LEAST 3 MONTHS of induction of therapy with corticosteroids and rituximab (either 1000 mg IV x 2 or 375 mg/m2 IV x 4) OR corticosteroids and cyclophosphamide (monthly IV or daily oral doses). They must be on no more than 5 mg daily of oral prednisone or equivalent. Complete remission is defined as a BVAS score = 0. Patients may be ANCA negative or positive at randomization. B cells are not depleted anymore: B cell recovery reaches 1% CD19+ B cells (enough to allow determination of CD5+ B cells with confidence). Exclusion Criteria: Patients who have had ≥ 2 relapses (defined as recurrence of any signs or symptoms attributable to active vasculitis) previously as patients with multiple prior relapses may be at higher risk of future relapse and require maintenance therapy Patients with persistent low-grade disease activity (grumbling disease defined as BVAS > 0 and ≤ 3) Patients with active systemic infections or deep space infections within the 3 months prior to screening. Patients participating in another clinical trial mandating maintenance therapy Patients with drug-induced ANCA vasculitis (e.g. levamisole-adulterated cocaine) Active tuberculosis, human immunodeficiency virus (HIV), hepatitis C virus or hepatitis B virus infections For women of child-bearing potential, pregnancy, breastfeeding, unwillingness or inability to comply with effective contraception Inability to come to scheduled visits

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects with normalized CD5+ B cells are thought to be at lower risk and relapse, and therefore may not need maintenance immunosuppression. The subjects in that group will be randomized to either maintenance immunosuppression vs close clinical observation without maintenance immunosuppression.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: low CD5+ /on maintenance<br>Subjects in remission with Cluster of Differentiation (CD)19+CD5+ lower than 43% will continue on maintenance immunosuppression (Maintenance Therapy Group)- no randomization. | Device: ENUMERATION OF CD5+ B Cells<br>* A blood test is done to assess what percentage of CD5+ is present within CD19+. The result is then used to guide choice of arm.<br>|
| Active Comparator: high CD5/ on maintenance<br>Subjects in remission with CD19+CD5+ 43% or greater, randomized to continue on maintenance immunosuppression (Maintenance Therapy Group) | Device: ENUMERATION OF CD5+ B Cells<br>* A blood test is done to assess what percentage of CD5+ is present within CD19+. The result is then used to guide choice of arm.<br>|
| Experimental: high CD5 / NO maintenance<br>Subjects in remission with CD19+CD5+ 43% or greater , randomized to NO maintenance immunosuppression (NO Maintenance Therapy Group) | Device: ENUMERATION OF CD5+ B Cells<br>* A blood test is done to assess what percentage of CD5+ is present within CD19+. The result is then used to guide choice of arm.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Relapse | The primary outcome measure is time to first relapse defined as recurrence of any signs or symptoms attributable to active vasculitis after a period of complete remission, with at least 2 minor or 1 major item on the BVAS score (BVAS≥2). Per protocol, complete remission is defined as a BVAS score = 0. Birmingham Vasculitis Activity Score for Wegener's Granulomatosis(BVAS, range 0-64). The total score is composed of 34 predefined items, units on a scale, grouped into 9 organ systems. Each item carries a weight from 1-3, depending on disease severity. A score of 0 indicates no disease activity; a higher score indicates worsening disease. | from complete remission to end of study, approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Relapse | severity (as determined by BVAS score) of relapse in each group | from complete remission to end of study, approximately 2 years | 
| Frequency of Relapse | frequency, as determined by number of relapse in each group | from complete remission to end of study, approximately 2 years | 
| Time to Positive ANCA | for patients who had a negative ANCA test, time to positive ANCA | from first negative ANCA test since start of study , if applicable- to end of study, maximum two years, as applicable | 
| Frequency of Infections | number of infections | from remission to end of study, approximately 2 years | 
| Number of Infections, categorized by severity | number of mild/moderate/serious infections | from remission to end of study, approximately 2 years | 
| Time to IL-10 secreting B regulatory cells > 45% or CD5+ B cells > 43% of total B cells | time to IL-10 secreting B regulatory cells > 45% or CD5+ B cells > 43% of total B cells | from enrollment to end of study, approximately 2.5 to 3 years |