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

This study has been withdrawn prior to enrollment.

(the study failed to enroll any patient and sponsor wished to stop.)

Sponsor:

Collaborators:

Alexion Pharmaceuticals

National Institutes of Health (NIH)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Information provided by (Responsible Party):

Patrick Nachman, MD, University of North Carolina, Chapel Hill

ClinicalTrials.gov Identifier:

NCT01275287

First received: December 13, 2010

Last updated: March 29, 2013

Last verified: March 2013

History of Changes

Purpose

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.

Condition	Intervention	Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis	Drug: Standard of care treatment Drug: eculizumab	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Targeting Complement Activation in Antineutrophil Cytoplasmic Autoantibodies (ANCA)-Vasculitis

Resource links provided by NLM:

MedlinePlus related topics: Vasculitis

Drug Information available for: Cyclophosphamide Eculizumab

U.S. FDA Resources

Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:

Birmingham Vasculitis Activity Score (BVAS) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
Change in disease activity as measured by BVAS at 12 weeks.

Secondary Outcome Measures:

Complement levels elevation [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
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
Birmingham Vasculitis Activity Score(BVAS) [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
Percent of patients with a BVAS =0 at 3 months
Normalisation of complement activation [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
Normalization of complement activation at 4 weeks, 8, 12, 24, 36 and 52 weeks
Change in complement levels [ Time Frame: from baseline to week 12 ] [ Designated as safety issue: No ]
Change in complement levels between groups from baseline to week 12
change in complement levels 2 [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
Change in these complement levels with treatment and decrease in disease activity for each patient
Birmingham Vasculitis Activity Score (BVAS) 2 [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
Mean BVAS at 24, 36 and 52 weeks

Enrollment:	0
Study Start Date:	May 2011
Study Completion Date:	December 2012
Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Standard of care Standard of care for ANCA vasculitis treatment	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 Name: cytoxan
Experimental: Eculizumab arm Standard of care for ANCA vasculitis + eculizumab treatment	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 Name: Soliris

Arms

Assigned Interventions

Active Comparator: Standard of care

Standard of care for ANCA vasculitis treatment

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 Name: cytoxan

Experimental: Eculizumab arm

Standard of care for ANCA vasculitis + eculizumab treatment

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 Name: Soliris

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

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01275287

Locations

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

Sponsors and Collaborators

University of North Carolina, Chapel Hill

Alexion Pharmaceuticals

National Institutes of Health (NIH)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Principal Investigator:

Patrick H Nachman, MD

UNC Kidney Center

More Information

No publications provided

Responsible Party:	Patrick Nachman, MD, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:	NCT01275287 History of Changes
Other Study ID Numbers:	10-2218, P01DK058335
Study First Received:	December 13, 2010
Last Updated:	March 29, 2013
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board United States: Federal Government

Keywords provided by University of North Carolina, Chapel Hill:

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Complement Activation

Additional relevant MeSH terms:

Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Systemic Vasculitis
Autoimmune Diseases
Immune System Diseases

Autoantibodies
Complement System Proteins
Antibodies, Antineutrophil Cytoplasmic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2013

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