ANCA Associated Vasculitis
Conditions
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. Cluster of Differentiation 20 (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 of 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.
Interventions
DEVICEENUMERATION 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.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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 Birmingham Vasculitis Activity Score (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Relapse | from complete remission to end of study, approximately 2 years | 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 (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
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Relapse | from complete remission to end of study, approximately 2 years | Frequency, as determined by number of relapse in each group. Per protocol relapse is defined as BVAS \>/= 2; however for reporting purposes relapse was defined as BVAS \>/= 1 because the participant was treated based on the clinical relapse. |
| Severity of Relapse | from complete remission to end of study, approximately 2 years | Severity of relapse as determined by number of major relapse in each group. Major relapse is defined as involving a major organ |
| Time to Positive ANCA | from first negative ANCA test since start of study , if applicable- to end of study, maximum two years, as applicable | For participants who had a negative ANCA test, time to positive ANCA |
| Number of Participants Who Experience Relapse | from complete remission to end of study, approximately 2 years | Relapse in each group was determined using the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis(BVAS, range 0-64). The total score is composed of 34 predefined items grouped into 9 organ systems. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. A score of 0 indicates no disease activity; a higher score indicates worsening disease. Per protocol relapse is defined as BVAS \>/= 2; however for reporting purposes relapse was defined as BVAS \>/= 1 because the participant was treated based on the clinical relapse. |
| Number of Infections, Categorized by Severity | from remission to end of study, approximately 2 years | number of mild/moderate/severe infections |
| Time to Interleukin (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 | Time to IL-10 secreting B regulatory cells \> 45% or CD5+ B cells \> 43% of total B cells |
| Frequency of Infections | from remission to end of study, approximately 2 years | Frequency as determined by the number of infections |
Countries
United States
Participant flow
Pre-assignment details
Individuals who signed informed consent and then completed all baseline measurement procedures and remained eligible were considered enrolled and were randomized. One consented participant experienced a Serious Adverse Event and was withdrawn before randomization and another consented participant was screen failed because they were not in remission.
Participants by arm
| Arm | Count |
|---|---|
| Low CD5+ /on Maintenance Participants in remission with Cluster of Differentiation (CD)19+CD5+ lower than 43% will continue on maintenance immunosuppression (Maintenance Therapy Group)- no randomization.
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. | 1 |
| High CD5/ on Maintenance Participants in remission with CD19+CD5+ 43% or greater, randomized to continue on maintenance immunosuppression (Maintenance Therapy Group)
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. | 4 |
| High CD5 / NO Maintenance Participants in remission with CD19+CD5+ 43% or greater , randomized to NO maintenance immunosuppression (NO Maintenance Therapy Group)
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. | 2 |
| Total | 7 |
Baseline characteristics
| Characteristic | Total | High CD5 / NO Maintenance | Low CD5+ /on Maintenance | High CD5/ on Maintenance |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Anti-Neutrophilic Cytoplasmic Antibodies (ANCA) Positive at Enrollment | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 2 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 7 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 4 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 1 / 1 | 1 / 4 | 2 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 1 | 0 / 4 | 0 / 2 | 1 / 2 |
Outcome results
Primary
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 (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.
Time frame: from complete remission to end of study, approximately 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low CD5+ /on Maintenance | Time to First Relapse | 7.1 months | Standard Deviation 0 |
| High CD5/ on Maintenance | Time to First Relapse | NA months | — |
| High CD5 / NO Maintenance | Time to First Relapse | NA months | — |
Secondary
Frequency of Infections
Frequency as determined by the number of infections
Time frame: from remission to end of study, approximately 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low CD5+ /on Maintenance | Frequency of Infections | 0 infections |
| High CD5/ on Maintenance | Frequency of Infections | 0 infections |
| High CD5 / NO Maintenance | Frequency of Infections | 1 infections |
Secondary
Frequency of Relapse
Frequency, as determined by number of relapse in each group. Per protocol relapse is defined as BVAS \>/= 2; however for reporting purposes relapse was defined as BVAS \>/= 1 because the participant was treated based on the clinical relapse.
Time frame: from complete remission to end of study, approximately 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low CD5+ /on Maintenance | Frequency of Relapse | 1 relapse |
| High CD5/ on Maintenance | Frequency of Relapse | 0 relapse |
| High CD5 / NO Maintenance | Frequency of Relapse | 0 relapse |
Secondary
Number of Infections, Categorized by Severity
number of mild/moderate/severe infections
Time frame: from remission to end of study, approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low CD5+ /on Maintenance | Number of Infections, Categorized by Severity | Moderate | 0 infection |
| Low CD5+ /on Maintenance | Number of Infections, Categorized by Severity | Severe | 0 infection |
| Low CD5+ /on Maintenance | Number of Infections, Categorized by Severity | Mild | 0 infection |
| High CD5/ on Maintenance | Number of Infections, Categorized by Severity | Mild | 0 infection |
| High CD5/ on Maintenance | Number of Infections, Categorized by Severity | Moderate | 0 infection |
| High CD5/ on Maintenance | Number of Infections, Categorized by Severity | Severe | 0 infection |
| High CD5 / NO Maintenance | Number of Infections, Categorized by Severity | Severe | 0 infection |
| High CD5 / NO Maintenance | Number of Infections, Categorized by Severity | Mild | 0 infection |
| High CD5 / NO Maintenance | Number of Infections, Categorized by Severity | Moderate | 1 infection |
| Non-Randomized | Number of Infections, Categorized by Severity | Mild | 0 infection |
| Non-Randomized | Number of Infections, Categorized by Severity | Severe | 0 infection |
| Non-Randomized | Number of Infections, Categorized by Severity | Moderate | 0 infection |
Secondary
Number of Participants Who Experience Relapse
Relapse in each group was determined using the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis(BVAS, range 0-64). The total score is composed of 34 predefined items grouped into 9 organ systems. Each item has a specified weight of either 3 or 1, depending on whether it reflects major or minor disease activity. A score of 0 indicates no disease activity; a higher score indicates worsening disease. Per protocol relapse is defined as BVAS \>/= 2; however for reporting purposes relapse was defined as BVAS \>/= 1 because the participant was treated based on the clinical relapse.
Time frame: from complete remission to end of study, approximately 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low CD5+ /on Maintenance | Number of Participants Who Experience Relapse | 1 Participants |
| High CD5/ on Maintenance | Number of Participants Who Experience Relapse | 0 Participants |
| High CD5 / NO Maintenance | Number of Participants Who Experience Relapse | 0 Participants |
Secondary
Severity of Relapse
Severity of relapse as determined by number of major relapse in each group. Major relapse is defined as involving a major organ
Time frame: from complete remission to end of study, approximately 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low CD5+ /on Maintenance | Severity of Relapse | Minor | 1 Participants |
| Low CD5+ /on Maintenance | Severity of Relapse | Major | 0 Participants |
| Low CD5+ /on Maintenance | Severity of Relapse | No relapse | 0 Participants |
| High CD5/ on Maintenance | Severity of Relapse | Minor | 0 Participants |
| High CD5/ on Maintenance | Severity of Relapse | Major | 0 Participants |
| High CD5/ on Maintenance | Severity of Relapse | No relapse | 4 Participants |
| High CD5 / NO Maintenance | Severity of Relapse | Major | 0 Participants |
| High CD5 / NO Maintenance | Severity of Relapse | No relapse | 2 Participants |
| High CD5 / NO Maintenance | Severity of Relapse | Minor | 0 Participants |
Secondary
Time to Interleukin (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
Time frame: from enrollment to end of study, approximately 2.5 to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low CD5+ /on Maintenance | Time to Interleukin (IL)-10 Secreting B Regulatory Cells > 45% or CD5+ B Cells > 43% of Total B Cells | NA months |
| High CD5/ on Maintenance | Time to Interleukin (IL)-10 Secreting B Regulatory Cells > 45% or CD5+ B Cells > 43% of Total B Cells | NA months |
| High CD5 / NO Maintenance | Time to Interleukin (IL)-10 Secreting B Regulatory Cells > 45% or CD5+ B Cells > 43% of Total B Cells | NA months |
Secondary
Time to Positive ANCA
For participants 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low CD5+ /on Maintenance | Time to Positive ANCA | NA months |
| High CD5/ on Maintenance | Time to Positive ANCA | NA months |
| High CD5 / NO Maintenance | Time to Positive ANCA | NA months |