Abatacept for Treating Adults With Giant Cell Arteritis and Takayasu's Arteritis

Study Overview
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Brief Summary
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Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are diseases that cause swelling of the arteries in the head, neck, upper body, and arms. TAK specifically affects the aorta, the largest blood vessel in the body, and its branches. Therapies are available to improve the symptoms of GCA and TAK, but relapse often occurs, and better treatments are needed. Abatacept is a drug that interacts with certain cells in the body that are involved with GCA and TAK. This study will evaluate the effectiveness of abatacept in treating GCA and TAK and preventing disease relapse.

Detailed Description
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GCA and TAK both cause inflammation in the lining of the arteries, which can interfere with the body's ability to carry oxygen to areas that need it. Symptoms of GCA include headaches, jaw pain, and blurred or double vision. Serious symptoms that occur less commonly are blindness and stroke. TAK symptoms include fever, fatigue, weight loss, arthritis, and non-specific aches and pains. There may also be tenderness near affected arteries. Researchers believe that GCA and TAK are diseases that are controlled by the body's immune system. Activated T-cells, specifically, are critical to the origin and development of these diseases. Abatacept is a medication that modulates the signal required for T-cell activation. This study will evaluate the safety and effectiveness of abatacept in treating GCA and TAK and preventing disease relapse. Participation in this study may last up to 4 years. Participants will receive abatacept intravenously on specified days during Months 1, 2, and 3. They will also receive daily prednisone, which will be started at a dose of 40 to 60mg, then tapered to 20mg by Month 3, and finally further tapered until discontinuation is reached. At Month 3, participants who have achieved remission will be randomly assigned under double-blind conditions to either continue abatacept or be switched to placebo infusions. Both treatments will be given once a month at study visits. Blood samples will also be collected at the monthly study visits to conduct laboratory-based studies. Participants who remain in remission will continue to receive abatacept or placebo monthly until the common closing date, defined as 12 months after enrollment of the 33rd participant for each disease.

Official Title
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Concurrent Pilot Studies in Giant Cell Arteritis and Takayasu's Arteritis to Examine the Safety, Efficacy, and Immunologic Effects of Abatacept (CTLA4-Ig) in Large Vessel Vasculitis

Conditions
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Takayasu's Arteritis, Giant Cell Arteritis

Intervention / Treatment
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* Drug: Abatacept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of GCA or TAK (defined below) History of active GCA or TAK within the past 2 months Age of 15 years or older Willing to use an effective means of birth control throughout the study Specific Inclusion Criteria for Participants with GCA: Participants must meet three of the following five criteria, including either Criterion 4 or 5: Age at disease onset was equal to or greater than 50 years Disease onset was recent or experiencing a new type of localized pain in the head Erythrocyte sedimentation rate greater than 40mm in the first hour, as determined using the Westergren method Temporal artery abnormality (i.e., temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries) Temporal artery or large vessel biopsy showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cell or characteristic changes of large vessel stenosis or aneurysm by arteriography Specific Inclusion Criteria for Participants with TAK: Presence of abnormalities that are consistent with TAK identified using arteriography, plus at least one of the following criteria: Age at disease onset was less than 50 years Pain in the legs or arms Decreased brachial artery pulse (one or both arteries) Difference of more than 10mm Hg in blood pressure between the arms Bruit over subclavian arteries or aorta Exclusion Criteria: Evidence of active infection (including chronic infection) Pregnant or breastfeeding HIV infected, hepatitis C infected, or a positive hepatitis B surface antigen Inability to comply with study guidelines Inability to provide informed consent Cytopenia, as defined by a platelet count of less than 80,000/mm3, an absolute neutrophil count of less than 1,500/mm3, and hematocrit less than 20% Insufficient kidney function, as defined by a serum creatinine of more than 3 mg/dL or creatinine clearance of 20 ml/min or less Other uncontrolled disease that could prevent safe study completion History of any malignant neoplasm except adequately treated basal or squamous cell carcinoma of the skin or solid tumors treated with curative therapy and disease-free for at least 5 years Receipt of an investigational agent or device within 30 days prior to study entry A live vaccination within 4 weeks prior to study entry Presence of a positive tuberculin skin test with induration of at least 5mm Radiographic evidence suggestive of tuberculosis Poor tolerability of blood draws or lack of adequate access to veins for medication administration and blood draws History of treatment with rituximab within 12 months prior to study entry or history of treatment with rituximab more than 12 months prior to study entry, where the B lymphocyte count has not returned to normal History of treatment with infliximab within the past 49 days, adalimumab within the past 28 days, or etanercept within the past 21 days. Presence of any of the following diseases or conditions: Microscopic polyangiitis Churg-Strauss syndrome Polyarteritis nodosa Cogan's syndrome Behcet disease Sarcoidosis Kawasaki disease Tuberculosis or atypical mycobacterial infection Deep fungal infection Lymphoma, lymphomatoid granulomatosis, or other type of malignancy that mimics vasculitis Cryoglobulinemic vasculitis Systemic lupus erythematosus Rheumatoid arthritis Mixed connective tissue disease or any overlap autoimmune syndrome

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A and C<br>This is a randomized withdrawal design protocol. All participants will receive abatacept and prednisone (a glucocorticoid) for the first 3 months. Abatacept will be given intravenously on selected days. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Month 3, and finally further tapered until discontinuation is reached. At Month 3, participants who have achieved remission will be randomly assigned under double-blind conditions to receive monthly infusions of either abatacept or placebo. Participants who are assigned to abatacept at this point will be in Group A for giant cell arteritis and Group C for Takayasu arteritis. | Drug: Abatacept<br>* Participants will receive a fixed dose of abatacept, approximating 10mg per kilogram of body weight. The following dosing rules will be followed: Participants weighing less than 60kg will receive 500mg of abatacept. Participants weighing 60 to 100kg will receive 750mg of abatacept. Participants weighing more than 100kg will receive 1000mg of abatacept. Abatacept will be administered in a 30-minute intravenous infusion on Days 1, 15, 29 (Month 1) and at Month 2. In the absence of toxicity or relapse, participants will remain on abatacept at the same dosage until randomization at Month 3. After randomization, only Group A (giant cell arteritis) and Group C (Takayasu arteritis) participants will continue on abatacept.<br>* Other names: Orencia;|
| Placebo Comparator: B and D<br>This is a randomized withdrawal design protocol. All participants will receive abatacept and prednisone (a glucocorticoid) for the first 3 months. Abatacept will be given intravenously on selected days. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Month 3, and finally further tapered until discontinuation is reached. At Month 3, participants who have achieved remission will be randomly assigned under double-blind conditions to receive monthly infusions of either abatacept or placebo. Participants who are assigned to placebo at this point will be in Group B for giant cell arteritis and Group D for Takayasu arteritis. | Drug: Abatacept<br>* Participants will receive a fixed dose of abatacept, approximating 10mg per kilogram of body weight. The following dosing rules will be followed: Participants weighing less than 60kg will receive 500mg of abatacept. Participants weighing 60 to 100kg will receive 750mg of abatacept. Participants weighing more than 100kg will receive 1000mg of abatacept. Abatacept will be administered in a 30-minute intravenous infusion on Days 1, 15, 29 (Month 1) and at Month 2. In the absence of toxicity or relapse, participants will remain on abatacept at the same dosage until randomization at Month 3. After randomization, only Group A (giant cell arteritis) and Group C (Takayasu arteritis) participants will continue on abatacept.<br>* Other names: Orencia;Drug: Placebo<br>* Placebo abatacept infusions will be given monthly after random assignment at Month 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome - Relapse-free Survival (RFS) | Relapse: presence of active disease occurring after a period of remission Remission: absence of active disease Active disease defined by clinical features or imaging or both: Clinical features: 1 or more of the following attributed to GCA/TAK: Sustained fever of >38 C for > 1 week Vascular pain/tenderness > 1 day, non-fleeting Headache a) present > 1 day b) non-fleeting c) not relieved with analgesics d) not typical for pre-existing headaches Ischemic retinopathy, optic neuropathy, or visual loss Tongue/jaw pain and/or claudication TIA or stroke Extremity claudication Musculoskeletal symptoms + ESR of > 40 mm/hr or CRP above the normal limit Malaise/fatigue + ESR of > 40 mm/hr or CRP above the normal limit Other symptoms/signs due to GCA/TAK requiring reinstitution/increase in GC Imaging features • Development of new vascular stenosis or aneurysm in new vascular territories as seen by MRI/MRA or arteriogram | Weeks 0 to 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vasculitis, Arteritis, Takayasu's, Temporal Arteritis, Abatacept