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

Primary Purpose

ANCA Associated Vasculitis

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

ENUMERATION OF CD5+ B Cells

About this trial

This is an interventional treatment trial for ANCA Associated Vasculitis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of North Carolina at Chapel HillRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

low CD5+ /on maintenance

high CD5/ on maintenance

high CD5 / NO maintenance

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Severity of Relapse

severity (as determined by BVAS score) of relapse in each group

Frequency of Relapse

frequency, as determined by number of relapse in each group

Time to Positive ANCA

for patients who had a negative ANCA test, time to positive ANCA

Frequency of Infections

number of infections

Number of Infections, categorized by severity

number of mild/moderate/serious infections

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

Full Information

NCT ID

NCT03906227

First Posted

April 4, 2019

Last Updated

January 23, 2023

Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT03906227

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 28, 2019 (Actual)

Primary Completion Date

December 2027 (Anticipated)

Study Completion Date

June 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

ANCA Associated Vasculitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

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)

Allocation

Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

low CD5+ /on maintenance

Arm Type

Active Comparator

Arm Description

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

Arm Title

high CD5/ on maintenance

Arm Type

Active Comparator

Arm Description

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

Arm Title

high CD5 / NO maintenance

Arm Type

Experimental

Arm Description

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

Intervention Type

Device

Intervention Name(s)

ENUMERATION OF CD5+ B Cells

Intervention Description

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.

Primary Outcome Measure Information:

Title

Time to First Relapse

Description

Time Frame

from complete remission to end of study, approximately 2 years

Secondary Outcome Measure Information:

Title

Severity of Relapse

Description

severity (as determined by BVAS score) of relapse in each group

Time Frame

from complete remission to end of study, approximately 2 years

Title

Frequency of Relapse

Description

frequency, as determined by number of relapse in each group

Time Frame

from complete remission to end of study, approximately 2 years

Title

Time to Positive ANCA

Description

for patients who had a negative ANCA test, time to positive ANCA

Time Frame

from first negative ANCA test since start of study , if applicable- to end of study, maximum two years, as applicable

Title

Frequency of Infections

Description

number of infections

Time Frame

from remission to end of study, approximately 2 years

Title

Number of Infections, categorized by severity

Description

number of mild/moderate/serious infections

Time Frame

from remission to end of study, approximately 2 years

Title

Time to IL-10 secreting B regulatory cells > 45% or CD5+ B cells > 43% of total B cells

Description

time to IL-10 secreting B regulatory cells > 45% or CD5+ B cells > 43% of total B cells

Time Frame

from enrollment to end of study, approximately 2.5 to 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Anne Froment

Phone

(919) 445-2622

anne_froment@med.unc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Caroline Poulton

Phone

(919) 445-2636

Caroline_jennette@med.unc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Vimal Derebail, MD

Organizational Affiliation

University of North Carolina, Chapel Hill

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of North Carolina at Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599-7155

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Vimal K Derebail, MD

Phone

919-966-2561

vimal_derebail@med.unc.edu

First Name & Middle Initial & Last Name & Degree

Anne Froment

Phone

919-445-2622

anne_froment@med.unc.edu

First Name & Middle Initial & Last Name & Degree

Vimal K Derebail, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

IPD Sharing Time Frame

9 to 36 months following publication

IPD Sharing Access Criteria

approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and data use/sharing agreement with UNC.

Citations:

PubMed Identifier

25372085

Citation

Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quemeneur T, Blanchard-Delaunay C, Godmer P, Puechal X, Carron PL, Hatron PY, Limal N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231.

Results Reference

result

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

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