ANCA Associated Vasculitis, Granulomatosis With Polyangiitis, Microscopic Polyangiitis
Conditions
Keywords
Granulomatosis with Polyangiitis, Microscopic Polyangiitis, PR3-ANCA, ANCA-associated Vasculitis
Brief summary
The purpose of this study is to evaluate the efficacy and safety of obinutuzumab for the treatment of proteinase 3 Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (PR3-AAV).
Interventions
DRUGObinutuzumab
1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15
DRUGRituximab
1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15
Sponsors
Mayo Clinic
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Fulfillment of the definitions of the Second Chapel Hill Consensus Conference for ANCA-associated vasculitis (either granulomatosis with polyangiitis or microscopic polyangiitis). * Positivity for ANCA, directed against proteinase-3 (PR3) * Severe newly-diagnosed disease or severe relapsing disease. Severe relapsing disease is defined as at least one major BVAS/WG item or a score ≥ 3 and the investigator deems standard treatment for severe disease is necessary. * Minimum BVAS/WG of 3 * Relapsing patients must have B cells detectable in the peripheral blood. * Patients must have completed COVID19 vaccination (including booster if eligible) at least 4 weeks prior to enrollment with a positive spike protein antibody test result. Patients who have recovered from COVID19 prior to screening with a positive spike protein antibody test result but have not been vaccinated are also eligible. * Female subjects of childbearing potential who are not sterile must agree to use an acceptable method of contraception for 18 months after the last dose of infusion medication. Male subjects who are not sterile whose female partners are of childbearing potential must agree to use an acceptable method of contraception for 180 days after the last dose of infusion medication. * Females of childbearing potential include any female who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (to be considered postmenopausal, the patient must have had amenorrhea for \>12 consecutive months). * Acceptable methods of contraception include the use of at least two of the following: 1) intrauterine device; 2) hormonal contraceptives for at least 30 days prior to first dose infusion (oral, injectable, implant or ring); 3) barrier contraceptives (condom or diaphragm) with spermicide; or 4) abstinence.
Exclusion criteria
* Diagnosis with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) as defined by the Chapel Hill Consensus Conference. * Positive serum assays for ANCA directed against myeloperoxidase (MPO-ANCA) * Non-severe AAV, defined as disease that does not justify treatment with both B cell depletion and a four-month glucocorticoid taper. * Any of the co-morbidities: * Allergies: a history of severe allergic reactions to human or chimeric monoclonal antibodies or murine protein. * Infection (systemic): an active systemic infection at screening visit * Infection (deep space): have been diagnosed as having a deep-space infection, such as osteomyelitis, septic arthritis, or pneumonia complicated by empyema or lung abscesses, within 6 months prior to the screening visit * Infection (blood borne): active hepatitis B or active hepatitis C or a documented history of HIV, hepatitis B, or hepatitis C * Infection (history): History of recurrent significant infection or history of recurrent bacterial infections * Liver disease: acute or chronic liver disease that is deemed sufficiently severe to impair their ability to participate in the trial. * Renal disease: a history of documented anti-glomerular basement membrane disease (anti-GBM disease). * Malignancy: Active or history of malignancy in the last 5 years. Individuals with squamous cell or basal cell skin carcinomas and individuals with cervical carcinoma in situ may be enrolled if they have received curative surgical treatment. * Active COVID-19 infection. * Uncontrolled disease: evidence of glucocorticoid dependent disease (such as asthma, COPD, psoriasis or IBD, etc.) requiring consistently greater than 10 mg of prednisone for disease control which might affect endpoint assessment or, * Other uncontrolled diseases, including any uncontrolled psychiatric disorders, drug and alcohol abuse, that could interfere with participation in the trial according to the protocol. * Diagnosis of human anti-chimeric antibodies (HACA) formation. * Subjects who are premenopausal and are: * Pregnant on the basis of a serum pregnancy test, * Breastfeeding, or * Do not agree to use effective method(s) of contraception * Use of prohibited medications: They have used any of the prohibited medication listed in Section 5.9.1. * Plasma exchange: They have been treated with plasma exchange within the 3 months preceding the screening visit. * History of intolerance to rituximab or other chimeric monoclonal antibodies (e.g., infliximab). * Recent vaccination: They have had a live vaccine fewer than 4 weeks (28 days) before or during randomization (vaccination with live vaccine through the end of study participation is contraindicated). * Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients to Achieve Both Complete Remission and Seronegativity for ANCA. | 6 months | Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. Seronegativity for ANCA is defined as a negative test for antibodies directed against serine proteinase 3 (i.e., a negative PR3-ANCA assay). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients to Achieve Sustained Complete Remission 6 Months | 6 months | Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. |
| Number of Patients to Achieve Sustained Complete Remission 12 Months | 12 months | Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. |
| Number of Patients to Achieve Sustained Complete Remission 18 Months | 18 months | Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORUlrich Specks, MD
Mayo Clinic
Participant flow
Recruitment details
Trial was discontinued after enrollment of the first 6 patients because support was withdrawn by Genentech as enrollment lagged behind the projected timeline.
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Dose of Obinutuzumab Subjects who have clinical diagnoses of either granulomatosis with polyangiitis or microscopic polyangiitis received two intravenous doses of obinutuzumab
Obinutuzumab: 1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15 | 2 |
| Intravenous Dose of Rituximab Subjects who have clinical diagnoses of either granulomatosis with polyangiitis or microscopic polyangiitis received two intravenous doses of rituximab
Rituximab: 1000 mg per infusion given approximately two weeks apart, on day 1 and on day 15 | 4 |
| Total | 6 |
Baseline characteristics
| Characteristic | Intravenous Dose of Obinutuzumab | Total | Intravenous Dose of Rituximab |
|---|---|---|---|
| Age, Continuous | 54 years | 53.3 years | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 6 Participants | 4 Participants |
| Region of Enrollment United States | 2 participants | 6 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 4 |
| other Total, other adverse events | 2 / 2 | 4 / 4 |
| serious Total, serious adverse events | 1 / 2 | 0 / 4 |
Outcome results
Primary
Number of Patients to Achieve Both Complete Remission and Seronegativity for ANCA.
Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper. Seronegativity for ANCA is defined as a negative test for antibodies directed against serine proteinase 3 (i.e., a negative PR3-ANCA assay).
Time frame: 6 months
Population: Terminated study due lack of funding. Data was not collected nor analyzed due to lack of funding. Only one subject in each arm reached 6 months. Data was not collected nor analyzed for 1 subject in the Intravenous dose of obinutuzumab and 3 subjects in the Intravenous dose of rituximab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Dose of Obinutuzumab | Number of Patients to Achieve Both Complete Remission and Seronegativity for ANCA. | 0 Participants |
| Intravenous Dose of Rituximab | Number of Patients to Achieve Both Complete Remission and Seronegativity for ANCA. | 0 Participants |
Secondary
Number of Patients to Achieve Sustained Complete Remission 12 Months
Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper.
Time frame: 12 months
Population: Terminated study due lack of funding. Data was not collected nor analyzed due to lack of funding. Data was not collected nor analyzed for 2 subjects in the Intravenous dose of obinutuzumab and 4 subjects in the Intravenous dose of rituximab.
Secondary
Number of Patients to Achieve Sustained Complete Remission 18 Months
Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper.
Time frame: 18 months
Population: Terminated study due lack of funding. Data was not collected nor analyzed due to lack of funding. Data was not collected nor analyzed for 2 subjects in the Intravenous dose of obinutuzumab and 4 subjects in the Intravenous dose of rituximab.
Secondary
Number of Patients to Achieve Sustained Complete Remission 6 Months
Complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 without glucocorticoids beyond the prescribed prednisone taper.
Time frame: 6 months
Population: Terminated study due lack of funding. Data was not collected nor analyzed due to lack of funding. Only one subject in each arm reached 6 months. Data was not collected nor analyzed for 1 subject in the Intravenous dose of obinutuzumab and 3 subjects in the Intravenous dose of rituximab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Dose of Obinutuzumab | Number of Patients to Achieve Sustained Complete Remission 6 Months | 1 Participants |
| Intravenous Dose of Rituximab | Number of Patients to Achieve Sustained Complete Remission 6 Months | 0 Participants |