Wegener's Granulomatosis
Conditions
Keywords
Vasculitis, Relapse, Wegener's, Treatment
Brief summary
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.
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.
Interventions
DRUGAbatacept
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.
Sponsors
Office of Rare Diseases (ORD)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Rare Diseases Clinical Research Network
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Abatacept - Number of Participants With Adverse Events | Measured continuously from the screening visit through to the 6 month post-treatment study visit, up to 3 years and 4 months. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Remission | Measured monthly until common closing or early termination,up to 3 years and 4 months. | 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. |
| Disease Improvement | Measured monthly until common closing or early termination, up to 3 years and 4 months. | 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. |
| Meeting Common Closing | Number assessed at the time of common closing, up to 3 years and 4 months. | The number of subjects that reached the common closing date. |
| Disease Relapse | Measured monthly until common closing or early termination, up to 3 years and 4 months. | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in February 2008 and the final subject was enrolled in June 2010. Subjects were recruited through the clinical practices of each site investigator.
Pre-assignment details
At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then signed the informed consent form.
Participants by arm
| Arm | Count |
|---|---|
| Open-label Abatacept Participants received abatacept intravenously at study visits on Days 1, 15, and 29, and then once a month thereafter until common closing or early termination.
Abatacept : A participant's abatacept dose was based on body weight and remained 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 was administered in a 30-minute intravenous infusion. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Open-label Abatacept |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 45.1 years STANDARD_DEVIATION 16.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 20 |
| serious Total, serious adverse events | 7 / 20 |
Outcome results
Primary
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.
Time frame: Measured continuously from the screening visit through to the 6 month post-treatment study visit, up to 3 years and 4 months.
Population: This study intended to examine safety and to explore preliminary signal for efficacy of abatacept in Wegener's granulomatosis. The sample size of 20 was based upon a sufficient number of subjects to begin such pilot explorations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Serious adverse events | 7 participants |
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Non-serious adverse events | 16 participants |
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Infection | 14 participants |
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Infusion related (systemic) | 1 participants |
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Infusion related( intravenous site reaction) | 1 participants |
| Open-label Abatacept | Safety of Abatacept - Number of Participants With Adverse Events | Cytopenia | 4 participants |
Secondary
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.
Time frame: Measured monthly until common closing or early termination, up to 3 years and 4 months.
Population: This study intended to examine safety and to explore preliminary signal for efficacy of abatacept in Wegener's granulomatosis. The sample size of 20 was based upon a sufficient number of subjects to begin such pilot explorations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Abatacept | Disease Improvement | 18 participants |
Secondary
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.
Time frame: Measured monthly until common closing or early termination, up to 3 years and 4 months.
Population: This study intended to examine safety and to explore preliminary signal for efficacy of abatacept in Wegener's granulomatosis. The sample size of 20 was based upon a sufficient number of subjects to begin such pilot explorations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Abatacept | Disease Relapse | 3 participants |
Secondary
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.
Time frame: Measured monthly until common closing or early termination,up to 3 years and 4 months.
Population: This study intended to examine safety and to explore preliminary signal for efficacy of abatacept in Wegener's granulomatosis. The sample size of 20 was based upon a sufficient number of subjects to begin such pilot explorations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Abatacept | Disease Remission | 16 participants |
Secondary
Meeting Common Closing
The number of subjects that reached the common closing date.
Time frame: Number assessed at the time of common closing, up to 3 years and 4 months.
Population: This study intended to examine safety and to explore preliminary signal for efficacy of abatacept in Wegener's granulomatosis. The sample size of 20 was based upon a sufficient number of subjects to begin such pilot explorations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Abatacept | Meeting Common Closing | 14 participants |