Exploring Durable Remission With Rituximab in Antineutrophil Cytoplasmic Antibody(ANCA)-Associated Vasculitis

Study Overview
=================
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

Official Title
-----------------
Evaluating Clinical and Immunological Effects of Rituximab With Cyclophosphamide Compared to Rituximab Alone in AAV Patients

Conditions
-----------------
ANCA Associated Vasculitis

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: endoxan
* Drug: Methylprednisolone
* Drug: Prednisolone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects enrolled in the study must meet the following inclusion criteria: Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26 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 Positive test for anti-PR3 or anti-MPO (current or historic) 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 exclusion criteria: Pregnant or breast-feeding Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L) Active infection not compatible with start of remission-induction therapy in the opinion of the treating physician and/or investigator, e.g.: Serological evidence of viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication Have a historically positive HIV test or test positive at screening for HIV Have a history of a primary immunodeficiency Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study Have a neutrophil count of < 1.5x10E9/L Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing Have any other clinically significant abnormal laboratory value in the opinion of the investigator Required dialysis or plasma exchange within 12 weeks prior to screening Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening Immunization with a live vaccine 1 month before screening History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label, 1:1 randomized, prospective study between RTX with cyclophosphamide and RTX alone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab<br>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. | Drug: Rituximab<br>* 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.<br>* Other names: anti-cd20;Drug: Methylprednisolone<br>* 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.<br>* Other names: solumedrol;Drug: Prednisolone<br>* after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations<br>* Other names: corticosteroid;|
| Active Comparator: Rituximab plus low-dose cyclophosphamide<br>5.1.2. Cyclophosphamide 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. | Drug: Rituximab<br>* 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.<br>* Other names: anti-cd20;Drug: endoxan<br>* 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.<br>* Other names: cyclophosphamide;Drug: Methylprednisolone<br>* 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.<br>* Other names: solumedrol;Drug: Prednisolone<br>* after intravenous pulse methylprednisolone, oral prednisolone will be given at a dose of 1mg/kg daily and tapered according to the recommendations<br>* Other names: corticosteroid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of tailored RTX infusions | The primary outcome is the number of RTX infusions needed to maintain clinical remission over 2 years | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time | - time to a ANCA negative test | 2 years | 
| ANCA reappearance | - Percentage of patients that have ANCA return during follow-up | 2 years | 
| B cell depletion | - duration of B-cell depletion | 2 years | 
| Remission and relaps rate | - to compare disease controle between arms | 2 years | 
| Number of adverse events | - 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 | 2 years | 
| Quality of Life by AAV-PRO | assess quality of life by AAV-PRO | 2 years | 
| BVAS | Disease activity will be assessed by BVAS | 2 years | 
| concomitant immunosuppressants | Disease activity assessed by (the reduction of) concomitant immunosuppressants | 2 years | 
| Kidney function | Return of kidney function will be assessed. | 2 years | 
| Biomarker for inflammation | Disease activity assessed by ESR | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GPA, ANCA, Crescentic glomerulonephritis, systemic autoimmune disease, Renal failure, Renal insufficiency, small vessel vasculitis, MPA