RemiRit - Personalized immunosuppressive therapy with rituximab in the treatment of ANCA associated vasculitis - a randomized, multicenter clinical trial

Prior treatment

• Limited form of disease that does not require treatment with cyclophosphamide.
• Abuse of drugs, alcohol or other intoxicating substances.
• Vaccination with live vaccines within 4 weeks prior to screening.
• History of hemorrhagic cystitis, bone marrow hypoplasia or malignancy during treatment with cyclophosphamide.

Other illness

• Acute or chronic respiratory failure, not due to AAV.
• Documented history of antichimeric antibody formation after administration of monoclonal antibodies.
• Respiratory failure due to diffuse alveolar hemorrhage requiring mechanical ventilation.
• Diagnosis of disease associated with anti-glomerular basement membrane (anti-GBM) as defined by the Chapel Hill Consensus Conference.
• Active or history of cancer within the past 5 years, except for basal-cell carcinoma of the skin and carcinoma in situ of cervix in patients who have received radical treatment.
• Severe heart failure (New York Heart Association Class IV) or severe uncontrolled heart disease not due to AAV.
• Infections: a. Active and chronic viral, bacterial, fungal or parasitic infection b. Active or latent tuberculosis c. Active or chronic hepatitis B d. Active or chronic hepatitis C e. Diagnosed HIV infection.
• History of severe allergic reactions to human or chimeric monoclonal antibodies or mouse proteins.
• History of hypersensitivity to the active substance or any excipient of the investigational medicinal products (cyclophosphamide or rituximab).
• History of intolerance to any of the investigational medicinal products (cyclophosphamide or rituximab).
• History of allergy to drugs or other substances which, in the opinion of the Investigator is a contraindication to participation in the study.
• Acute or chronic liver disease, not due to AAV, which in the opinion of the Investigator is a contraindication to participation in the study.
• History or presence of other relevant diseases that, in the opinion of the Investigator may adversely affect the patient's participation in the study.
• Current history of urinary tract obstruction.

Lab values

• Medications being taken: a. Rituximab and other drugs that cause B-lymphocyte depletion within 6 months prior to screening, b. Cyclophosphamide within 6 months prior to screening, except when oral cyclophosphamide is included up to 7 days prior to screening and discontinued no later than the day of screening, c. Infliximab within 3 months prior to screening, d. Adalimumab within 2 months prior to screening, e. Etanercept within 1 month prior to screening.
• Diagnosis of AAV with simultaneous presence of both MPO-ANCA and PR3-ANCA antibodies in serum.
• Screening findings: a. Leukopenia defined as a white blood cell (WBC) count below 4000/mm3, b. Neutropenia defined as a neutrophil count less than 1500/mm3, c. Thrombocytopenia defined as a platelet count (PLT) less than 100000/mm3, d. Hemoglobin (Hgb) less than 8.0 g/dl, e. AST or ALT elevations greater than 2.5 x GGN, not due to AAV, f. Severe immunoglobulin deficiency defined as IgG less than 400 mg/dL or IgA less than 10 mg/dL, g. Positive HBsAg, h. Positive anti-HCV result, i. Positive QuantiFERON-TB Gold test result, j. Positive anti-HIV 1 or anti-HIV 2

Age

• Positive pregnancy test performed among women of childbearing age at screening or Visit 1.

Other

• Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) as defined by the Chapel Hill Consensus Conference.
• Diagnosis of AAV limited to the kidney, without involvement of other organs.
• Pregnancy or planning a pregnancy during the study and 12 months after the study.
• Breastfeeding or planning to breastfeed during the study and 12 months after completion of the study.
• Participation in another clinical trial.
• Lack of patient compliance.
• Congenital or acquired immunodeficiency.
• Bone marrow aplasia.

• Written informed consent of the patient to participate in the clinical trial.
• Consent to prophylactically intake of Entecavir in case of a positive total anti-Hbc result with HBsAg.
• Age ≥ 18 years.
• Diagnosis of AAV, including granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) as defined by the Chapel Hill Consensus Conference.
• New diagnosis or exacerbation of AAV.
• High AAV activity defined as ≥ 3 points on the BVAS/WG scale.
• Positive PR3-ANCA or MPO-ANCA at screening or within 30 days prior to screening.
• Discontinuation of current immunosuppressive and immunomodulatory agents, including mycophenolate mofetil, azathioprine, methotrexate and leflunomide, no later than the day of screening.
• Use of highly effective contraception by women of childbearing potential during the study and 12 months after the last administration of the investigational medicinal product.
• Use of high barrier contraception by men with female partners of childbearing potential throughout the study and 6 months after the last administration of an investigational medicinal product.