ANCA Associated Vasculitis
Conditions
Keywords
ANCA, Crescentic glomerulonephritis, systemic autoimmune disease, Renal failure, Renal insufficiency, small vessel vasculitis, GPA, MPA
Brief summary
Most recent insights in the treatment for patients with ANCA-associated vasculitis (AAV) have demonstrated that 'tailored' maintenance treatment with rituximab (RTX) is effective to achieve durable remission of disease. As such, RTX re-treatment can be tailored on the basis of relevant clinical and immunological parameters in AAV patients. Now, the present study intends to evaluate whether combining rituximab with cyclophosphamide is superior to current standard of care with rituximab only to induce a favorable clinical and immunological state in AAV patients and can thereby reduce the number of tailored re-treatments with rituximab.
Detailed description
Objectives: The primary objective is to prove that the combination of RTX and low-dose CYC reduces the number of RTX infusions needed to maintain clinical remission over 2 years. The secondary objectives are measurements for minimal residual auto-immunity (MRA) such as time to ANCA seronegativity, proportion of seronegativity, time to ANCA return, proportion of ANCA return, duration of B-cell depletion and the composition of the memory B-cell and plasma cell populations. Other secondary objectives are the potential association between MRA and disease flares, and the evaluation of (severe) adverse events, cost-effectiveness and quality of life Study design: open-label, multicenter, 1:1 randomized, prospective study Study population: Adult AAV patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have 'generalised disease' and a positive ANCA-test for anti-PR3 or anti-MPO. Intervention: In addition to standard of care corticosteroid therapy, AAV patients will be randomized to receive either standard induction therapy with 2 infusions of RTX 1000 mg or induction therapy combining 2 infusions of RTX 1000 mg with 6 infusions of low dose intravenous cyclophosphamide 500mg. Thereafter, as part of standard of care patients will receive tailored RTX re-treatment as maintenance therapy. Main study parameters: AAV patients will be evaluated for the cumulative number of events for tailored RTX retreatments needed to maintain clinical remission over 2 years. Also, AAV patients will be evaluated for MRA by prospectively and consecutively studying ANCA levels and B-cell depletion by standard flowcytometry at predefined timepoints. Additionally, the study will perform safety and toxicity monitoring according to WHO toxicity criteria and evaluate the clinical response, the number of moderate and severe flares during study follow-up, the cost-effectiveness, and the quality of life of patients. Study duration: 2 years
Interventions
DRUGRituximab
Patients will be intravenously treated with Rituximab 1000mg (or biosimilar) in the first week and receive a 2nd dosage of 1000mg 14 days later. Before every infusion of Rituximab patients will receive intravenous methylprednisolone 100mg together with oral acetaminophen 1000 mg and and intravenous Tavegil 2 mg. At any time during the study, a rituximab biosimilar is allowed as a substitute for the bio-originator rituximab.
DRUGendoxan
Patients will be intravenously treated with a total of 6 infusions of cyclophosphamide 500mg every 2 weeks. Before every infusion of cyclophosphamide patients will receive intravenous granisetron to prevent nausea.
DRUGMethylprednisolone
Patients are given 1-3 pulses of 500mg methylprednisolone i.v. up to a maximum cumulative dose of 3000mg, taking into account any doses of intravenous methylprednisolone administered within 12 weeks prior to screening.
DRUGPrednisolone
after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations
Sponsors
Leiden University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects enrolled in the study must meet the following inclusion criteria: 1. Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26 2. Aged at least 18 years, with newly-diagnosed or relapsed AAV with 'generalised disease', defined as involvement of at least one major organ (e.g. kidney, lung, heart, peripheral or central nervous system), requiring induction treatment with cyclophosphamide or rituximab 3. Positive test for anti-PR3 or anti-MPO (current or historic) 4. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol
Exclusion criteria
Subjects will be excluded from participation if they meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of tailored RTX infusions | 2 years | The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time | 2 years | \- time to a ANCA negative test |
| ANCA reappearance | 2 years | \- Percentage of patients that have ANCA return during follow-up |
| B cell depletion | 2 years | \- duration of B-cell depletion |
| Remission and relaps rate | 2 years | \- to compare disease controle between arms |
| Biomarker for inflammation | 2 years | Disease activity assessed by ESR |
| Quality of Life by AAV-PRO | 2 years | assess quality of life by AAV-PRO |
| BVAS | 2 years | Disease activity will be assessed by BVAS |
| concomitant immunosuppressants | 2 years | Disease activity assessed by (the reduction of) concomitant immunosuppressants |
| Kidney function | 2 years | Return of kidney function will be assessed. |
| Number of adverse events | 2 years | \- to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria, time to immune reconstitution and recording of infectious events |
Countries
Netherlands
Contacts
Primary ContactYKO Teng, MD, PhD
Outcome results
None listed