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

Study Purpose

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.#46; 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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 85 Years
Gender	All

More Inclusion & Exclusion 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03906227
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University of North Carolina, Chapel Hill
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Vimal Derebail, MD
Principal Investigator Affiliation	University of North Carolina, Chapel Hill
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, NIH
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	ANCA Associated Vasculitis

Additional Details

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.#46;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.

Arms & Interventions

Arms

Active Comparator: low CD5+ /on maintenance

Subjects in remission with Cluster of Differentiation (CD)19+CD5+ lower than 43% will continue on maintenance immunosuppression (Maintenance Therapy Group)- no randomization.

Active Comparator: high CD5/ on maintenance

Subjects in remission with CD19+CD5+ 43% or greater, randomized to continue on maintenance immunosuppression (Maintenance Therapy Group)

Experimental: high CD5 / NO maintenance

Subjects in remission with CD19+CD5+ 43% or greater , randomized to NO maintenance immunosuppression (NO Maintenance Therapy Group)

Interventions

Device: - ENUMERATION OF CD5+ B Cells

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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Chapel Hill, North Carolina

Status

Recruiting

Address

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599-7155

Site Contact

Vimal K Derebail, MD

[email protected]

919-966-2561

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