Abatacept in Treating Adults With Mild Relapsing Wegener's Granulomatosis

A Multi-Center, Open-label Pilot Study of Abatacept (CTLA4-Ig) in the Treatment of Mild Relapsing Wegener's Granulomatosis

Wegener's granulomatosis (WG) is a rare disease that causes inflammation of blood vessels, or vasculitis. It may involve many different parts of the body, but typically affects the upper and lower respiratory tract and kidneys. The purpose of this study is to determine the safety and effectiveness of the medication abatacept in treating adults with mild relapsing WG.

Study Overview

• Status: Completed
• Conditions: Wegener's Granulomatosis
• Intervention / Treatment: Drug: Abatacept

Detailed Description

Current standard treatment for WG involves various medications and is based on disease severity. Unfortunately, more than 50% of people experience a relapse after remission, placing them at risk for additional organ damage and medication toxicity. To prevent this, safer and more effective treatments for mild relapses are needed. Several studies have shown that activated T cells, a type of white blood cell important in regulating immune responses, play a role in WG. Abatacept, an immunoglobulin-based medication approved by the FDA to treat rheumatoid arthritis, acts by preventing T-cell activation and may be useful in treating mild relapses of WG. The purpose of this study is to determine the safety and effectiveness of abatacept in treating adults with mild relapsing WG.

Participants will receive abatacept intravenously at study visits on Days 1, 15, and 29, and then once a month thereafter. A participant's abatacept dose is based on body weight and will remain the same throughout the study. Participants who are receiving maintenance immunosuppressive medications consisting of methotrexate, azathioprine, or mycophenolate mofetil at the time of enrollment will remain on these medications without dosage increase or reduction. Eligible participants may be on up to prednisone 15mg daily at the time of relapse. Following the development of relapse, participants may be treated with up to prednisone 30mg daily if necessary, but must to be back to the same dose that they had been on prior to relapse by Month 2. All study visits include medication review, physical exam, blood and urine collection, and questionnaires. A chest x-ray, computed tomography (CT) scan of the chest and sinuses, and lung function testing will occur at some study visits. Participants whose symptoms did not improved by Month 2 will be taken off abatacept. Any participants undergoing early termination or, after common closing, will undergo three follow-up study visits at 1, 3, and 6 months after the end of treatment.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • The Johns Hopkins Vasculitis Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic College of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of WG, meeting at least 2 of the 5 modified American College of Rheumatology (ACR) criteria. More information about this criterion can be found in the protocol.

• Relapse of WG within the past 28 days where disease activity is confined to one or more of the following sites and where the symptoms/signs are of such a nature that the usual treatment would consist of the reinstitution or increase in GC to no more than prednisone 30mg daily and/or an increase or addition of a second immunosuppressive agent other than CYC (more specific information about this criterion can be found in the protocol):

  1. Sinonasal disease
  2. Oral mucosa ulceration
  3. Skin disease
  4. Musculoskeletal disease
  5. Pulmonary parenchymal disease
  6. Mild ocular disease
  7. Subglottic inflammation without significant stenosis
  8. Otic disease
  9. Breast involvement
  10. Urogenital involvement
  11. Other mild disease
• Age of 15 years or older
• Willing and able to undergo treatment and attend follow-up visits
• Willing to use effective forms of contraception throughout the study

Exclusion Criteria:

• Disease involvement that does not meet the criteria for mild disease. More information about this criterion can be found in the protocol.
• Disease activity that would usually be treated first with cyclophosphamide
• Presence of disease activity for which the investigator would normally treat the participant with more than prednisone 30 mg daily.
• Receiving cyclophosphamide at study entry
• Treatment with prednisone at a dose of more than 15 mg daily at the time of relapse. Subjects will be eligible if prednisone was initiated or dose increased in the period between relapse and study enrollment provided that the prednisone dose was 15 mg daily or less at the time when the relapse occurred, the prednisone dosage was increased no higher than 30 mg daily following the recognition of relapse, and that the dosage increase was made no more than 28 days prior to enrollment.
• Active infection
• HIV infected, hepatitis C virus infected, or positive for hepatitis B
• Unable to follow through with study participation
• Cytopenia, defined as platelet count less than 80,000/mm3, absolute neutrophil count less than 1500/mm3, OR hematocrit less than 20%
• Kidney insufficiency
• Use of illegal drugs
• Any other uncontrolled disease that would prevent participation
• History of cancer. More information about this criterion can be found in the protocol.
• Received an investigational medication or procedure within 30 days of study entry
• Received a live vaccine within 4 weeks of study entry
• Positive tuberculin skin test. More information about this criterion can be found in the protocol.
• Tuberculosis as indicated by radiographic evidence
• Past treatment with rituximab within the past 12 months, or past treatment with rituximab more than 12 months ago where the B lymphocyte count has not returned to normal
• Certain other diseases. More information about this criterion can be found in the protocol.
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Participants will receive abatacept intravenously at study visits on Days 1, 15, and 29, and then once a month thereafter.	Drug: Abatacept; A participant's abatacept dose depended on body weight and will remain the same throughout the study: 500 mg of abatacept for body weight less than 60 kg; 750 mg of abatacept for body weight between 60 and 100 kg; 1000 mg of abatacept for body weight greater than 100 kg Abatacept is administered in a 30-minute intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Abatacept - Number of Participants With Adverse Events	This study examined the safety profile of this agent when used in Wegener's granulomatosis. Information was gathered on all adverse events with specific events being identified in the protocol for analysis that included the following: Infection; Infusion reactions; Cytopenias; Transaminase elevation; Skin reactions; GI side effects; Malignancy All adverse events were reportable for this study.	Measured continuously from the screening visit through to the 6 month post-treatment study visit, up to 3 years and 4 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Remission	Disease remission was measured by a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0. The BVAS/WG is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63.	Measured monthly until common closing or early termination,up to 3 years and 4 months.
Disease Improvement	Disease improvement was measured by a reduction in the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG). The BVAS/WG is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63.	Measured monthly until common closing or early termination, up to 3 years and 4 months.
Meeting Common Closing	The number of subjects that reached the common closing date.	Number assessed at the time of common closing, up to 3 years and 4 months.
Disease Relapse	Disease relapse was measured by a rise in the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of greater than or equal to 1 after achieving remission. The BVAS/WG is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63.	Measured monthly until common closing or early termination, up to 3 years and 4 months.

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Rare Diseases Clinical Research Network; Office of Rare Diseases (ORD)
• Investigators: Principal Investigator: Carol A. Langford, MD, MHS, The Cleveland Clinic; Principal Investigator: Peter A. Merkel, MD, MPH, Boston University

Publications and helpful links

General Publications

• Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005 Sep 15;353(11):1114-23. doi: 10.1056/NEJMoa050524. Erratum In: N Engl J Med. 2005 Nov 24;353(21):2311.
• Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Am J Med. 2003 Apr 15;114(6):463-9. doi: 10.1016/s0002-9343(03)00077-9.
• Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61. doi: 10.1056/NEJMoa041884.
• Langford CA, Monach PA, Specks U, Seo P, Cuthbertson D, McAlear CA, Ytterberg SR, Hoffman GS, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis. 2014 Jul;73(7):1376-9. doi: 10.1136/annrheumdis-2013-204164. Epub 2013 Dec 9.

Helpful Links

• Cleveland Clinic Center for Vasculitis Care and Research website

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: April 30, 2007
• First Submitted That Met QC Criteria: April 30, 2007
• First Posted (Estimate): May 2, 2007

Study Record Updates

• Last Update Posted (Estimate): January 18, 2016
• Last Update Submitted That Met QC Criteria: December 15, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Treatment; Vasculitis; Relapse; Wegener's
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Vasculitis; Lung Diseases, Interstitial; Systemic Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Granulomatosis with Polyangiitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: RDCRN 5522; U54AR057319 (U.S. NIH Grant/Contract)