Granulomatosis With Polyangiitis, Microscopic Polyangiitis
Conditions
Brief summary
The purpose of this pilot study is to test whether an 8-week course of glucocorticoids, combined with rituximab, is effective in treating ANCA-associated vasculitis.
Detailed description
The primary aim of this pilot study is to examine whether an 8 week course of glucocorticoids, in combination with rituximab, is effective in inducing and maintaining disease remission for up to 6 months in a subset of patients with ANCA-associated vasculitis (AAV) who have a more favorable prognosis. This pilot study will enroll 20 patients with active AAV. Close patient follow-up will insure that any patients who require courses of glucocorticoids longer than two months will receive longer therapy, if appropriate for their well-being.
Interventions
DRUGGlucocorticoids
Patients will begin prednisone therapy at a dose selected by the investigator or the treating physician with oral prednisone 60mg or 1mg/kg (if weight less than 60kg) or intravenous methylprednisolone, up to 1g/day for three days. Prednisone will be tapered over 8 weeks as follows: * 60mg for 2 weeks * 40mg for 2 weeks * 30mg for 1 week * 20mg for 1 week * 10mg for 1 week * 5mg for 1 week
DRUGRituximab
Rituximab will be administered in four weekly doses at 375mg/m2
Sponsors
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients ages 18-85 years old * Diagnosis of GPA or MPA according to the definitions of the Chapel Hill Consensus Conference * New diagnosis or disease flare with a Birmingham Vasculitis Activity Score/Wegener's granulomatosis (BVAS/WG) of \> 3
Exclusion criteria
* Renal disease in patients with PR3-ANCA as defined by any of the following: * Urinary red blood cell casts * Biopsy-proven glomerulonephritis * Increase in serum creatinine of \>30% over baseline * Severe renal disease in patients with MPO-ANCA as defined by both of the following: * Urinary red blood cell casts or biopsy-proven glomerulonephritis * Estimated glomerular filtration rate \< 30 ml/min/1.73m2 * Diffuse alveolar hemorrhage requiring ventilatory support * GC treatment for longer than 14 days prior to enrollment unless patient has been on a stable maintenance dose of prednisone at the time of the flare * Daily oral cyclophosphamide within 1 month prior to enrollment * Completed a remission induction course of cyclophosphamide or rituximab within 4 months of enrollment * Hepatitis B infection * HIV infection * History of anti-GBM disease * Other uncontrolled disease, including drug and alcohol abuse, that may interfere with the study * Pregnancy or breastfeeding * History of severe allergic reactions to human or chimeric monoclonal antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission | 6 months | We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. The primary outcome was disease remission off steroids at 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partial Remission | 8 weeks | Number of patients entering partial remission, defined as no new disease manifestations, no worsening of existing disease and BVAS/WG \< 3. |
| Sustained Complete Remission | 6 months | Number of patients entering sustained remission defined as BVAS/WG = 0, prednisone dose = 0 and no disease flares during the study period. |
| Limited Flares | 6 months | Number of limited flares defined as a new occurrence or worsening of one or more minor BVAS/WG items and a total BVAS/WG ≤ 3 |
| Disease Response | 4 weeks | Number of patients achieving disease response defined as, no new disease manifestations; no worsening of existing disease; stable or improved BVAS/WG score at 4 weeks. |
| Early Treatment Failures | 4 weeks | Number of early treatment failures defined as patients who have new or worsening disease manifestations assessed at 4 weeks after study entry |
| Vasculitis Damage Index (VDI) | 24 months | The Vasculitis Damage Index (VDI) is a single-page catalog of damage items separated into 11 groupings of items by organ system. There are a total of 60 items. Each item is recorded if it occurred since the onset of vasculitis, has been present for at least 3 months, or occurred at least 3 months ago. Each item of damage is scored as present (1) or absent (0), yielding a maximum score of 60. |
| Severe Flares | 6 months | Number of severe flares defined as flare with BVAS/WG \> 3 or experiencing one of the major BVAS/WG items |
Countries
United States
Participant flow
Recruitment details
* New diagnosis or flare of previously diagnosed disease in patients followed in the Massachusetts General Hospital (MGH) Rheumatology or Nephrology Units. * New diagnosis or flare of previously diagnosed disease in patients hospitalized at MGH.
Participants by arm
| Arm | Count |
|---|---|
| Glucocorticoids and Rituximab This is a single-arm trial. All patients receive both rituximab and glucocorticoids. The protocol calls for the discontinuation of prednisone within two months of the baseline visit.
Glucocorticoids: Patients will begin prednisone therapy at a dose selected by the investigator or the treating physician with oral prednisone 60mg or 1mg/kg (if weight less than 60kg) or intravenous methylprednisolone, up to 1g/day for three days.
Prednisone will be tapered over 8 weeks as follows:
* 60mg for 2 weeks
* 40mg for 2 weeks
* 30mg for 1 week
* 20mg for 1 week
* 10mg for 1 week
* 5mg for 1 week
Rituximab: Rituximab will be administered in four weekly doses at 375mg/m2 | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 6 |
Baseline characteristics
| Characteristic | Glucocorticoids and Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| anti-neutrophil cytoplasmic antibody (ANCA) myeloperoxidase (MPO) | 11 Participants |
| anti-neutrophil cytoplasmic antibody (ANCA) Negative | 2 Participants |
| anti-neutrophil cytoplasmic antibody (ANCA) proteinase (PR3) | 7 Participants |
| Birmingham Vasculitis Activity Score for Wegener's Granulomatosis(BVAS/WG) | 5 units on a scale |
| Disease group Granulomatosis with polyangiitis (GPA) | 14 Participants |
| Disease group Indeterminate | 0 Participants |
| Disease group Microscopic polyangiitis (MPA) | 6 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 0 / 20 |
| serious Total, serious adverse events | 11 / 20 |
Outcome results
Primary
Complete Remission
We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. The primary outcome was disease remission off steroids at 6 months.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Complete Remission | 14 Participants |
Secondary
Disease Response
Number of patients achieving disease response defined as, no new disease manifestations; no worsening of existing disease; stable or improved BVAS/WG score at 4 weeks.
Time frame: 4 weeks
Population: Number of patients having a disease response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Disease Response | 20 Participants |
Secondary
Early Treatment Failures
Number of early treatment failures defined as patients who have new or worsening disease manifestations assessed at 4 weeks after study entry
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Early Treatment Failures | 0 Participants |
Secondary
Limited Flares
Number of limited flares defined as a new occurrence or worsening of one or more minor BVAS/WG items and a total BVAS/WG ≤ 3
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Limited Flares | 2 Participants |
Secondary
Partial Remission
Number of patients entering partial remission, defined as no new disease manifestations, no worsening of existing disease and BVAS/WG \< 3.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Partial Remission | 20 Participants |
Secondary
Severe Flares
Number of severe flares defined as flare with BVAS/WG \> 3 or experiencing one of the major BVAS/WG items
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Severe Flares | 5 Participants |
Secondary
Sustained Complete Remission
Number of patients entering sustained remission defined as BVAS/WG = 0, prednisone dose = 0 and no disease flares during the study period.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucocorticoids and Rituximab | Sustained Complete Remission | 14 Participants |
Secondary
Vasculitis Damage Index (VDI)
The Vasculitis Damage Index (VDI) is a single-page catalog of damage items separated into 11 groupings of items by organ system. There are a total of 60 items. Each item is recorded if it occurred since the onset of vasculitis, has been present for at least 3 months, or occurred at least 3 months ago. Each item of damage is scored as present (1) or absent (0), yielding a maximum score of 60.
Time frame: 24 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Glucocorticoids and Rituximab | Vasculitis Damage Index (VDI) | 24 month VDI score | 0.5 units on a scale |
| Glucocorticoids and Rituximab | Vasculitis Damage Index (VDI) | Baseline VDI score | 0 units on a scale |