Targeting Complement Activation in Antineutrophil Cytoplasmic Autoantibodies (ANCA)-Vasculitis - Eculizumab

University of North Carolina (UNC)

Status and phase: Withdrawn; Phase 2

Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Treatments: Drug: eculizumab; Drug: Standard of care treatment

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT01275287

10-2218

P01DK058335 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The purpose of this research study is to see if Eculizumab (Soliris®) can safely be used in addition to conventional therapy in patients with active ANCA (Antineutrophil Cytoplasmic Autoantibodies ) vasculitis and lead to a more rapid decrease in disease activity.

ANCA vasculitis is an inflammation of the small vessels whereby ANCA antibodies inappropriately activate one's own white blood cells (neutrophils) and cause damage to the small blood vessels.

Full description

Recent laboratory studies have identified that an important pathway of inflammation called the "complement pathway" may play an important role in how Antineutrophil Cytoplasmic Autoantibodies (ANCA) cause damage to the blood vessels. Eculizumab is a monoclonal antibody that targets a key component of the complement pathway named C5, and blocks its activation.

In a mouse model of ANCA vasculitis, it has been shown that blocking C5 activation can block the development of vasculitis or greatly reduce its severity.

The researchers in this study would like to see if taking eculizumab, in addition to the drugs usually used to treat ANCA vasculitis, would be beneficial in treating ANCA vasculitis.

Currently, the conventional treatment of ANCA vasculitis consists of corticosteroids and cyclophosphamide. The corticosteroids are given as by vein (methylprednisolone) for 3 days followed by prednisone by mouth daily for about 4-5 months. Cyclophosphamide is typically given by vein every 4 weeks for at least 3 months, but sometimes longer depending on whether the vasculitis is still active or not. After the vasculitis is in remission, a maintenance treatment with azathioprine or mycophenolate mofetil may be used. For patients who cannot tolerate cyclophosphamide, or who have received it in large doses previously, another medication called rituximab may be used instead. However, patients who need rituximab or have recently been treated with rituximab cannot participate in this study.

The study drug, eculizumab, is Food and Drug Administration (FDA) approved for indications other than ANCA vasculitis. It is an investigational drug and it is NOT FDA-approved for the treatment of ANCA vasculitis.

In this study, eculizumab will be given in addition to the standard of care treatment for the patients that will be randomised to the eculizumab group.

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:• Patients with active Antineutrophil Cytoplasmic Autoantibodies (ANCA) glomerulonephritis and/or small vessel vasculitis with de novo or relapsing disease (BVAS≥5).

• Patients must have a current or a history of positive ANCA by the ELISA technique.
• De novo or relapsing disease requiring immunosuppression.
• Patients must have evidence of active glomerulonephritis as evidenced by the presence of glomerular hematuria (dysmorphic Red Blood Cells (RBCs) or RBC casts) with or without an increase in serum creatinine.
• Patients will be eligible within 10 days of commencing induction therapy (i.e., they may have already received pulse methylprednisolone and first dose of cyclophosphamide).

Exclusion Criteria:• Pregnancy or lactation, or women of child bearing potential who are not willing or able to comply with 2 contraceptive methods.

• Patients with severe renal failure: creatinine > 6 mg/dL or receiving hemodialysis and/or receiving plasmapheresis therapy.
• Patients with severe pulmonary hemorrhage requiring ventilation and/or plasmapheresis therapy.
• Patients with active bacterial or viral infection.
• Absolute neutrophils count < 1000/mm^3 to minimize the risk of infections
• Hemoglobin < 8.5 g/dL
• Prior therapy with a monoclonal antibody (for example rituximab)within the previous 6 months. Peripheral CD-20 B-cells count <= 1% due to rituximab even longer than 6 months.
• Severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy.
• History of infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV), HIV, tuberculosis or syphilis.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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0 participants in 2 patient groups

Standard of care

Active Comparator group

Description:

Standard of care for ANCA vasculitis treatment- depends on severity of disease and individual characteristics and medical history of each patient so this won't be described here.

Treatment:

Drug: Standard of care treatment

Eculizumab arm

Experimental group

Description:

Standard of care for ANCA vasculitis + eculizumab treatment Standard of care for ANCA vasculitis treatment- depends on severity of disease and individual characteristics and medical history of each patient so this won't be described here.

Treatment:

Drug: eculizumab