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

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.

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.