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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Intervention / Treatment: Drug: Standard of care treatment; Drug: eculizumab

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27510-7155
      • UNC Kidney Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care; 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.	Drug: Standard of care treatment; induction : pulse methyl prednisolone (7 mg/kg/day x3) then prednisone 1 mg/kg/day (not to exceed 60 mg/day) for 4 weeks, then taper over the following 12 weeks. Cyclophosphamide starting at 0.75 gm/m2 IV (decreased to 0.5 gm/m^2 for patients > than 70 or with estimated Glomerular Filtration Rate (eGFR) < 20 ml/min) to be titrated up to 1 gm/m^2 depending on the 2 week white blood count (WBC) nadir > 3000 cell/μL. Subsequent cyclophosphamide will be given every 4 weeks for at least 2 more doses. Once complete remission for 2 months, patient may be switched from cyclophosphamide to maintenance therapy with azathioprine 1.5-2 mg/kg/day for 6-9 months (to a total of 12 months of therapy) . For patients who cannot tolerate cyclophosphamide, or who have received it in large doses previously, another medication called rituximab may be used instead. However, if rituximab is indicated for the patient, he cannot participate in the study.; Other Names: cytoxan
Experimental: Eculizumab arm; 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.	Drug: eculizumab; In addition to conventional therapy, patients randomized to eculizumab will receive 600 mg by IV infusion over 35 minutes every 7 days for the first 4 weeks, then 900 mg by IV infusion for the fifth dose 7 days later (week 5), then 900 mg every 14 days thereafter, for a total of 9 doses (about 3 months of treatment). This dosing scheme is based on that used for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). The length of treatment is shorter than for PNH, based on a desire to target the addition of eculizumab to the period of maximal disease activity, while limiting the risks of infectious complications in this first pilot study.; Other Names: Soliris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birmingham Vasculitis Activity Score (BVAS)	Change in disease activity as measured by BVAS at 12 weeks.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complement levels elevation	Evaluation of complement levels at study entry to determine which may be elevated in active disease (Bb, C3a, C3d, C3d/C3, C4d, C5a or C5b-9	up to 52 weeks
Birmingham Vasculitis Activity Score(BVAS)	Percent of patients with a BVAS =0 at 3 months	up to 52 weeks
Normalisation of complement activation	Normalization of complement activation at 4 weeks, 8, 12, 24, 36 and 52 weeks	up to 52 weeks
Change in complement levels	Change in complement levels between groups from baseline to week 12	from baseline to week 12
change in complement levels 2	Change in these complement levels with treatment and decrease in disease activity for each patient	up to 52 weeks
Birmingham Vasculitis Activity Score (BVAS) 2	Mean BVAS at 24, 36 and 52 weeks	up to 52 weeks

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH); Alexion Pharmaceuticals
• Investigators: Principal Investigator: Patrick H Nachman, MD, UNC Kidney Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: December 13, 2010
• First Submitted That Met QC Criteria: January 11, 2011
• First Posted (Estimate): January 12, 2011

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: February 17, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement Activation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Autoimmune Diseases; Systemic Vasculitis; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 10-2218; P01DK058335 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: no plan too share data