Clinical trial NCT01275287: Targeting Complement Activation in Antineutrophil Cytoplasmic Autoantibodies (ANCA)-Vasculitis - Eculizumab
Official title: Targeting Complement Activation in Antineutrophil Cytoplasmic Autoantibodies (ANCA)-Vasculitis
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Keywords: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Complement Activation
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Alexion Pharmaceuticals, Inc.
name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2011-01-12
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Birmingham Vasculitis Activity Score (BVAS)
timeFrame: 12 weeks
Secondary outcomes:
measure: Complement levels elevation
timeFrame: up to 52 weeks
measure: Birmingham Vasculitis Activity Score(BVAS)
timeFrame: up to 52 weeks
measure: Normalisation of complement activation
timeFrame: up to 52 weeks
measure: Change in complement levels
timeFrame: from baseline to week 12
measure: change in complement levels 2
timeFrame: up to 52 weeks
measure: Birmingham Vasculitis Activity Score (BVAS) 2
timeFrame: up to 52 weeks
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: UNC Kidney Center
state: North Carolina
Study officials:
affiliation: UNC Kidney Center
name: Patrick H Nachman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bala MM, Malecka-Massalska TJ, Koperny M, Zajac JF, Jarczewski JD, Szczeklik W. Anti-cytokine targeted therapies for ANCA-associated vasculitis. Cochrane Database Syst Rev. 2020 Sep 29;9(9):CD008333. doi: 10.1002/14651858.CD008333.pub2.