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

• Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00556439
• Collaborator: The Cleveland Clinic (Other), Office of Rare Diseases (ORD) (NIH), Rare Diseases Clinical Research Network (Other)
• Enrollment: 97
• Locations: 10
• Arms: 2
• Duration (Months): 80
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Takayasu's Arteritis; Giant Cell Arteritis	Drug: Abatacept; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A and C 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; 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.; Other Names: Orencia
Placebo Comparator: B and D 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; 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.; Other Names: Orencia ; Drug: Placebo; Placebo abatacept infusions will be given monthly after random assignment at Month 3.

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	Johns Hopkins Medical Center	Baltimore	Maryland	United States	21224
3	Boston University	Boston	Massachusetts	United States	02118
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Hospital for Special Surgery	New York	New York	United States	10021
6	Cleveland Clinic	Cleveland	Ohio	United States	44195
7	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261
8	University of Utah	Salt Lake City	Utah	United States	84132
9	St. Joseph's Hospital	Hamilton	Ontario	Canada	L8P 3B3
10	Mt. Sinai Hospital Toronto	Toronto	Ontario	Canada	M5T 3L9

Sponsors and Collaborators

• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• The Cleveland Clinic
• Office of Rare Diseases (ORD)
• Rare Diseases Clinical Research Network

Investigators

• Principal Investigator: Carol A. Langford, MD, MHS, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Cleveland Clinic Center for Vasculitis Care and Research Web site

Publications

None provided.

• Responsible Party: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• ClinicalTrials.gov Identifier: NCT00556439
• Other Study ID Numbers: N01 AR070018; 268200700036C-5-0-1; HHSN2682007000036C; NCT00788268
• First Posted: Nov 12, 2007
• Last Update Posted: Feb 26, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): Vasculitis; Arteritis; Takayasu's; Temporal Arteritis; Abatacept
• Additional relevant MeSH terms: Polymyalgia Rheumatica; Giant Cell Arteritis; Arteritis; Takayasu Arteritis; Aortic Arch Syndromes; Abatacept

Study Results

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.

Arm/Group Title	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
Arm/Group Description	This is a randomized withdrawal design protocol. 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.	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.	This is a randomized withdrawal design protocol. 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.	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.
Period Title: Study Entry to Week 12
STARTED	49	0	34	0
COMPLETED	41	0	26	0
NOT COMPLETED	8	0	8	0
Period Title: Study Entry to Week 12
STARTED	20	21	11	15
COMPLETED	17	17	11	14
NOT COMPLETED	3	4	0	1

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	20	21	11	15	67
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 55%	3 14.3%	11 100%	15 100%	40 59.7%
>=65 years	9 45%	18 85.7%	0 0%	0 0%	27 40.3%
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	63.47	71.48	30.17	28.61	48.74
Sex: Female, Male (Count of Participants)
Female	16 80%	21 100%	9 81.8%	13 86.7%	59 88.1%
Male	4 20%	0 0%	2 18.2%	2 13.3%	8 11.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 9.1%	0 0%	1 1.5%
Not Hispanic or Latino	17 85%	21 100%	10 90.9%	14 93.3%	62 92.5%
Unknown or Not Reported	3 15%	0 0%	0 0%	1 6.7%	4 6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 4.8%	1 9.1%	3 20%	5 7.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 5%	1 4.8%	1 9.1%	0 0%	3 4.5%
White	19 95%	19 90.5%	8 72.7%	12 80%	58 86.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 9.1%	0 0%	1 1.5%
Region of Enrollment (participants) [Number]
Canada	6 30%	5 23.8%	3 27.3%	3 20%	17 25.4%
United States	14 70%	16 76.2%	8 72.7%	12 80%	50 74.6%

Outcome Measures

1. Primary Outcome

Title	Primary Outcome - Relapse-free Survival (RFS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	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
Arm/Group Description	This is a randomized withdrawal design protocol. 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.	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.	This is a randomized withdrawal design protocol. 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.	This is a randomized withdrawal design protocol. 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.
Measure Participants	20	21	11	15
Relapsed	10 50%	14 66.7%	8 72.7%	10 66.7%
Remained in remission	10 50%	7 33.3%	3 27.3%	5 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Abatacept in Giant Cell Arteritis, Group B - Placebo in Giant Cell Arteritis
	Comments	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.
	Type of Statistical Test	Other
	Comments	Kaplan-Meier curves of relapse free survival were constructed, and differences in treatment arms compared using the logrank test. The analysis of the primary outcome was based upon intent to treat.
Statistical Test of Hypothesis	p-Value	0.049
	Comments	The p value of 0.049 reflects comparison of relapse free survival of abatacept versus placebo in giant cell arteritis.
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group C - Abatacept in Takayasu Arteritis, Group D - Placebo in Takayasu Arteritis
	Comments	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.
	Type of Statistical Test	Other
	Comments	Kaplan-Meier curves of relapse free survival were constructed, and differences in treatment arms compared using the logrank test. The analysis of the primary outcome was based upon intent to treat.
Statistical Test of Hypothesis	p-Value	0.853
	Comments	The p value of 0.853 reflects comparison of relapse free survival of abatacept versus placebo in Takayasu arteritis.
	Method	Log Rank
	Comments

Adverse Events

Time Frame	Week 0 to end of study
Adverse Event Reporting Description	Toxicity grades were assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE). Expected or unexpected adverse events that were grade 1 were not collected or reported.
Arm/Group Title	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
Arm/Group Description	This is a randomized withdrawal design protocol. 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.		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.		This is a randomized withdrawal design protocol. 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.		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.
All Cause Mortality
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/11 (0%)		0/15 (0%)
Serious Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/20 (40%)		5/21 (23.8%)		5/11 (45.5%)		7/15 (46.7%)
Eye disorders
Ocular/visual - other	2/20 (10%)	2	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Retinal detachment	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Gastrointestinal disorders
Gastrointestinal - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Gastrointestinal - other	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Ulcer - GI	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Hemorrhage - GI	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	2/15 (13.3%)	2
General disorders
Pain - other	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Pain - other	0/20 (0%)	0	0/21 (0%)	0	2/11 (18.2%)	7	1/15 (6.7%)	1
Infections and infestations
Infection with normal ANC or grade 1 or 2 neutrophils	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Infection - other	0/20 (0%)	0	0/21 (0%)	0	2/11 (18.2%)	2	2/15 (13.3%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	2/15 (13.3%)	2
Investigations
Metabolic/laboratory - other	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Bone: spine-scoliosis	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Nervous system disorders
Syncope (fainting)	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Renal and urinary disorders
Renal/genitourinary - other	2/20 (10%)	2	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Urinary electrolyte wasting	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper respiratory - other	0/20 (0%)	0	2/21 (9.5%)	2	0/11 (0%)	0	0/15 (0%)	0
Dyspnea	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Dermatology /Skin - other	1/20 (5%)	1	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Surgical and medical procedures
Intraoperative-injury - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Vascular disorders
Thrombosis/thrombus/embolism	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Thrombosis/thrombus/embolism	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Vascular - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		15/21 (71.4%)		8/11 (72.7%)		14/15 (93.3%)
Blood and lymphatic system disorders
Blood and bone marrow - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Hemoglobin	3/20 (15%)	4	2/21 (9.5%)	3	0/11 (0%)	0	0/15 (0%)	0
Lymphopenia	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Hemoglobin	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	1/15 (6.7%)	1
Edema: limb	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Cardiac disorders
Cardiac arrhythmia - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Palpitations	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Vasovagal episode	0/20 (0%)	0	1/21 (4.8%)	3	0/11 (0%)	0	0/15 (0%)	0
Cardiac ischemia/infarction	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Hypertension	2/20 (10%)	2	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Cardiac general - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	1/15 (6.7%)	1
Hypertension	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	1/15 (6.7%)	1
Ear and labyrinth disorders
Hearing	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Tinnitus	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Endocrine disorders
Adrenal insufficiency	1/20 (5%)	1	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Endocrine - other	1/20 (5%)	1	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Hot flashes/flushes	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Hypothyroid	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Endocrine - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Eye disorders
Cataract	1/20 (5%)	2	2/21 (9.5%)	2	0/11 (0%)	0	0/15 (0%)	0
Ocular/Visual - other	1/20 (5%)	2	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Ocular/visual - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Gastrointestinal disorders
Colitis	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Constipation	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Dysphagia	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Gastrointestinal - other	1/20 (5%)	1	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Heartburn/dyspepsia	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Nausea	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Vomiting	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
General disorders
Fatigue	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Insomnia	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Weight gain	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Weight loss	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Pain	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Pain - other	1/20 (5%)	4	1/21 (4.8%)	1	0/11 (0%)	1	0/15 (0%)	0
Weight gain	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	3/15 (20%)	3
Pain	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	1/15 (6.7%)	1
Pain - other	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Immune system disorders
Allergic reaction/hypersensitivity	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Vasculitis	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Infections and infestations
Infection - other	5/20 (25%)	10	7/21 (33.3%)	10	0/11 (0%)	0	0/15 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils	2/20 (10%)	3	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Infection with unknown ANC	1/20 (5%)	2	2/21 (9.5%)	3	0/11 (0%)	0	0/15 (0%)	0
Infection - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	5	7/15 (46.7%)	17
Infection with normal ANC or Grade 1 or 2 neutrophils	0/20 (0%)	0	0/21 (0%)	0	3/11 (27.3%)	3	2/15 (13.3%)	9
Infection with unknown ANC	0/20 (0%)	0	0/21 (0%)	0	2/11 (18.2%)	3	2/15 (13.3%)	6
Investigations
ALT, SGPT	2/20 (10%)	2	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
AST, SGOT	1/20 (5%)	1	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Metabolic/laboratory - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
AST, SGOT	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	2/15 (13.3%)	2
Albumin, serum - low	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Calcium, serum - low	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Glucose, serum - high	0/20 (0%)	0	0/21 (0%)	0	2/11 (18.2%)	2	0/15 (0%)	0
Glucose, serum - low	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	2/15 (13.3%)	4
Metabolic/laboratory - other	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Sodium, serum - low	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Arthritis non-septic	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Fracture	2/20 (10%)	2	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Joint - function	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Musculoskeletal/Soft tissue - other	2/20 (10%)	5	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Fracture	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	0/15 (0%)	0
Nervous system disorders
Memory impairment	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Mood alteration	1/20 (5%)	2	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Dizziness	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Mood alteration	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Neurology - other	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1
Renal and urinary disorders
Renal/Genitourinary - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Pulmonary/Upper respiratory - other	1/20 (5%)	1	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Skin and subcutaneous tissue disorders
Dermatology - other	3/20 (15%)	4	0/21 (0%)	0	0/11 (0%)	0	0/15 (0%)	0
Ulceration	0/20 (0%)	0	1/21 (4.8%)	1	0/11 (0%)	0	0/15 (0%)	0
Dermatology/skin - other	0/20 (0%)	0	0/21 (0%)	0	1/11 (9.1%)	1	2/15 (13.3%)	2
Vascular disorders
Vascular - other	0/20 (0%)	0	0/21 (0%)	0	0/11 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

Small sample size, challenges in assessing disease activity in giant cell arteritis and Takayasu arteritis, 84.6% of patients with Takayasu arteritis were enrolled for the treatment of a disease relapse.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.