Giant Cell Arteritis, Takayasu's Arteritis
Conditions
Keywords
Vasculitis, Arteritis, Takayasu's, Temporal Arteritis, Abatacept
Brief summary
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
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.
Interventions
DRUGAbatacept
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.
DRUGPlacebo
Placebo abatacept infusions will be given monthly after random assignment at Month 3.
Sponsors
The Cleveland Clinic
Office of Rare Diseases (ORD)
Rare Diseases Clinical Research Network
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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: 1. Age at disease onset was equal to or greater than 50 years 2. Disease onset was recent or experiencing a new type of localized pain in the head 3. Erythrocyte sedimentation rate greater than 40mm in the first hour, as determined using the Westergren method 4. Temporal artery abnormality (i.e., temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries) 5. 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: 1. Age at disease onset was less than 50 years 2. Pain in the legs or arms 3. Decreased brachial artery pulse (one or both arteries) 4. Difference of more than 10mm Hg in blood pressure between the arms 5. 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: 1. Microscopic polyangiitis 2. Churg-Strauss syndrome 3. Polyarteritis nodosa 4. Cogan's syndrome 5. Behcet disease 6. Sarcoidosis 7. Kawasaki disease 8. Tuberculosis or atypical mycobacterial infection 9. Deep fungal infection 10. Lymphoma, lymphomatoid granulomatosis, or other type of malignancy that mimics vasculitis 11. Cryoglobulinemic vasculitis 12. Systemic lupus erythematosus 13. Rheumatoid arthritis 14. Mixed connective tissue disease or any overlap autoimmune syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Outcome - Relapse-free Survival (RFS) | Weeks 0 to 64 | 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 |
Countries
Canada, United States
Participant flow
Recruitment details
Participants with giant cell arteritis or Takayasu arteritis were recruited at 11 academic medical centers. For giant cell arteritis, the first participant was enrolled 2/2009 and the last participant was enrolled 1/2014. For Takayasu arteritis, the first participant was enrolled 2/2009 and the last participant was enrolled 11/2013.
Participants by arm
| Arm | Count |
|---|---|
| Group A - Abatacept in Giant Cell Arteritis This is a randomized withdrawal design protocol. All participants with giant cell arteritis will receive prednisone (a glucocorticoid) and abatacept for the first 12 weeks. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Week 12 and finally further tapered until discontinuation is reached at Week 28. Abatacept will be given intravenously on Day 1, Day 15, and Week 8 at a fixed dose approximating 10mg per kilogram of body weight. The following dosing rules for abatacept 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.
At Week 12, 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. | 20 |
| Group B - Placebo in Giant Cell Arteritis This is a randomized withdrawal design protocol. All participants with giant cell arteritis will receive prednisone (a glucocorticoid) and abatacept for the first 12 weeks. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Week 12 and finally further tapered until discontinuation is reached at Week 28. Abatacept will be given intravenously on Day 1, Day 15, and Week 8 at a fixed dose approximating 10mg per kilogram of body weight. The following dosing rules for abatacept 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.
At Week 12, 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. | 21 |
| Group C - Abatacept in Takayasu Arteritis This is a randomized withdrawal design protocol. All participants with Takayasu arteritis will receive prednisone (a glucocorticoid) and abatacept for the first 12 weeks. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Week 12 and finally further tapered until discontinuation is reached at Week 28. Abatacept will be given intravenously on Day 1, Day 15, and Week 8 at a fixed dose approximating 10mg per kilogram of body weight. The following dosing rules for abatacept 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.
At Week 12, 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 C. | 11 |
| Group D - Placebo in Takayasu Arteritis This is a randomized withdrawal design protocol. All participants with Takayasu arteritis will receive prednisone (a glucocorticoid) and abatacept for the first 12 weeks. Prednisone will be started at a dose of 40 to 60mg, then tapered to 20mg by Week 12 and finally further tapered until discontinuation is reached at Week 28. Abatacept will be given intravenously on Day 1, Day 15, and Week 8 at a fixed dose approximating 10mg per kilogram of body weight. The following dosing rules for abatacept 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.
At Week 12, 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 D. | 15 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| After Week 12 (Randomized Study Period) | Malignancy | 0 | 1 | 0 | 1 |
| After Week 12 (Randomized Study Period) | Physician Decision | 1 | 0 | 0 | 0 |
| After Week 12 (Randomized Study Period) | Severe infection | 1 | 0 | 0 | 0 |
| After Week 12 (Randomized Study Period) | Withdrawal by Subject | 1 | 3 | 0 | 0 |
| Study Entry to Week 12 | Lack of Efficacy | 5 | 0 | 6 | 0 |
| Study Entry to Week 12 | Malignancy | 0 | 0 | 1 | 0 |
| Study Entry to Week 12 | Physician Decision | 1 | 0 | 0 | 0 |
| Study Entry to Week 12 | Recurrent infection | 1 | 0 | 0 | 0 |
| Study Entry to Week 12 | Withdrawal by Subject | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Group A - Abatacept in Giant Cell Arteritis | Group B - Placebo in Giant Cell Arteritis | Group C - Abatacept in Takayasu Arteritis | Group D - Placebo in Takayasu Arteritis | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 18 Participants | 0 Participants | 0 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 3 Participants | 11 Participants | 15 Participants | 40 Participants |
| Age, Continuous | 63.47 Years | 71.48 Years | 30.17 Years | 28.61 Years | 48.74 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 21 Participants | 10 Participants | 14 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 19 Participants | 19 Participants | 8 Participants | 12 Participants | 58 Participants |
| Region of Enrollment Canada | 6 participants | 5 participants | 3 participants | 3 participants | 17 participants |
| Region of Enrollment United States | 14 participants | 16 participants | 8 participants | 12 participants | 50 participants |
| Sex: Female, Male Female | 16 Participants | 21 Participants | 9 Participants | 13 Participants | 59 Participants |
| Sex: Female, Male Male | 4 Participants | 0 Participants | 2 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 11 | 0 / 15 |
| other Total, other adverse events | 14 / 20 | 15 / 21 | 8 / 11 | 14 / 15 |
| serious Total, serious adverse events | 8 / 20 | 5 / 21 | 5 / 11 | 7 / 15 |
Outcome results
Primary
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
Time frame: Weeks 0 to 64
Population: The primary study endpoint was relapse-free survival (RFS). Kaplan-Meier curves of RFS were constructed for each stratum (giant cell arteritis and Takayasu arteritis), and differences in treatment arms compared using the logrank test. The analysis of the primary outcome was based upon intent to treat.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A - Abatacept in Giant Cell Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Relapsed | 10 Participants |
| Group A - Abatacept in Giant Cell Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Remained in remission | 10 Participants |
| Group B - Placebo in Giant Cell Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Remained in remission | 7 Participants |
| Group B - Placebo in Giant Cell Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Relapsed | 14 Participants |
| Group C - Abatacept in Takayasu Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Relapsed | 8 Participants |
| Group C - Abatacept in Takayasu Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Remained in remission | 3 Participants |
| Group D - Placebo in Takayasu Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Relapsed | 10 Participants |
| Group D - Placebo in Takayasu Arteritis | Primary Outcome - Relapse-free Survival (RFS) | Remained in remission | 5 Participants |
Comparison: The planned sample size was determined by the minimally clinically meaningful result (i.e., an approximate 30% improvement in relapse-free survival) to be detected utilizing a one-sided alpha of 0.1. Kaplan-Meier curves of RFS were constructed for each stratum, and differences in treatment arms compared using the logrank test. The analysis of the primary outcome was based upon intent to treat.p-value: 0.049Log Rank
Comparison: The planned sample size was determined by the minimally clinically meaningful result (i.e., an approximate 30% improvement in relapse-free survival) to be detected utilizing a one-sided alpha of 0.1. Kaplan-Meier curves of RFS were constructed for each stratum, and differences in treatment arms compared using the logrank test. The analysis of the primary outcome was based upon intent to treat.p-value: 0.853Log Rank