Phase IIIB Subcutaneous Abatacept Monotherapy Study

Rheumatoid Arthritis (RA) Clinical Trial

Official title:

A Phase IIIb, Multi-center, Stratified, Open-Label Study to Evaluate the Immunogenicity, Steady State Trough Level, and Safety of Subcutaneous Abatacept (BMS-188667) in Subjects With Rheumatoid Arthritis Administered With or Without Background Methotrexate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00547521
• Other study ID #: IM101-173
• Status: Completed
• Phase: Phase 3
• First received: October 19, 2007
• Last updated: March 13, 2015
• Start date: December 2007
• Est. completion date: February 2014

Study information

• Verified date: March 2015
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

To evaluate safety and immunogenicity of abatacept when used with or without methotrexate in the absence of an IV loading dose of abatacept

Recruitment information / eligibility

• Status: Completed
• Enrollment: 119
• Est. completion date: February 2014
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of Rheumatoid Arthritis

• Subjects Global Disease Assessment of greater than equal to 20 mm on a visual analog scale

• Discontinue all Biologics and Disease-modifying antirheumatic drugs (DMARDS) except for methotrexate

Exclusion Criteria:

• Received treatment with rituximab

• Subjects who have received treatment with immunoadsorbtion columns (such as Prosorba columns), mycophenolate mofetil (Cellcept®), cyclosporine A or other calcineurin inhibitors, or D-Penicillamine

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis (RA)

Intervention

Drug:
• abatacept
solution, subcutaneous injection, 125 mg/kg, weekly, 106 days in short term; long term is open
• Methotrexate (MTX)
Participants who were currently receiving methotrexate at a stable dose = 10 mg for at least 4 weeks

Locations

Country	Name	City	State
Australia	Local Institution	Hobart	Tasmania
Australia	Local Institution	Malvern	Victoria
Australia	Local Institution	Maroochydore	Queensland
Mexico	Local Institution	D.f.	Distrito Federal
Mexico	Local Institution	Guadalajara	Jalisco
South Africa	Local Institution	Berea	Kwa Zulu Natal
South Africa	Local Institution	Panorama	Western Cape
United States	East Penn Rheumatology Associates	Bethlehem	Pennsylvania
United States	Regional Rheumatology Associates	Binghamton	New York
United States	Boulder Medical Center	Boulder	Colorado
United States	Low Country Rheumatology, Pa	Charleston	South Carolina
United States	Columbia Arthritis Center	Columbia	South Carolina
United States	Altoona Center For Clinical Research	Duncansville	Pennsylvania
United States	Rheumatic Disease Center	Glendale	Wisconsin
United States	Physicians East, Pa	Greenville	North Carolina
United States	Rheumatology Associates Of North Alabama	Huntsville	Alabama
United States	Medical Towers South	Louisville	Kentucky
United States	Coastal Clinical Research Inc	Mobile	Alabama
United States	Westroads Medical Group	Omaha	Nebraska
United States	The Arthritis Center	Palm Harbor	Florida
United States	Stanford University School Of Medicine	Palo Alto	California
United States	Healthcare Research Consultants	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Mexico,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (Enzyme-linked Immunosorbent Assay [ELISA] Method) at Day 113 of the ST Study	ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.	Day 113	No
Primary	Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (ELISA Method) Over Time During the ST Study	ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.	Day 15, 29, 43, 57, 85,113 and 28, 56, and 85 days post last dose.	No
Primary	Number of Participants With Positive Anti-abatacept Responses to Abatacept (Meso-Scale Discovery [MSD] Electrochemiluminescence [ECL] Assay Method) Over Time During the ST Study	The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. It is more sensitive and has a higher drug tolerance than ELISA method. For the anti-abatacept antibody ECL (MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.	Day 15, 29, 43, 57, 85,113 and 28, 56 and 85 days post last dose.	No
Primary	Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for ELISA Results)	ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.	Day 113.	No
Primary	Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for MSD Results)	The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. It is more sensitive and has a higher drug tolerance than the ELISA method. For anti-abatacept antibody ECL (MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.	Day 113.	No
Primary	Cross Tabulations of the Number of Participants With Positive and Negative Immunogenicity Status at Baseline and Each Visit During the ST Study (for ELISA Results)	ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.	Baseline and on day 15, 29, 43, 57, 85 and 113	No
Primary	Cross Tabulations of the Number of Participants With Positive and Negative Immunogenicity Status at Baseline and Each Visit During the ST Study (for MSD Results)	The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum . It is more sensitive and has a higher drug tolerance than the ELISA method. For anti-abatacept antibody ECL(MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.	Baseline and day 15, 29, 43, 57, 85 and 113.	No
Secondary	Change From Baseline in DAS28-CRP Score at End of 4-month (Day 113) of the ST Study	DAS28-CRP is a continuous variable which is a composite of 4 variables: the number of tender joint out of 28, the number of swollen joint out of 28, C-reactive protein (CRP) in milligrams/Liter (mg/L) and subject assessment of disease activity measure on a VAS of 100mm. DAS 28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * VAS + 0.96.	Baseline and Month 4 (Day113).	No
Secondary	Number of Participants With Clinically Meaningful Improvement at End of 4-month (Day 113) of the ST Study	A clinically meaningful improvement is defined as a greater than or equal to 1.2 reduction in DAS28-CRP score from baseline.	Day 113.	No
Secondary	Change From Baseline in Physical Functioning (HAQ-DI) at End of the 4-month Treatment Period (Day 113) of the ST Study	HAQ-DI takes into account participant's use of aids or devices or assistance in scoring algorithm for a disability category. The questionnaire includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The questions are evaluated on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score is calculated by summing worst scores in each domain and dividing by the number of domains answered.	Baseline and Month 4 (Day 113).	No
Secondary	Change From Baseline in All HAQ-DI Components at End of the 4-month Treatment Period (Day 113) of the ST Study	HAQ-DI takes into account participant's use of aids or devices or assistance in scoring algorithm for a disability category. The questionnaire includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The questions are evaluated on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score is calculated by summing worst scores in each domain and dividing by the number of domains answered.	Baseline and Month 4 (Day113).	No
Secondary	Cross Tabulations of Number of Participants With Positive and Negative Status for RF at Day 113 With Baseline, in the ST Study	RF is an autoantibody that is usually present in the serum of people with rheumatoid arthritis. The cut-point value for seroconversion was 15 IU/mL (>= 15 IU/mL resulted in a positive result). Cross-tabulation of frequency of seroconversion of RF at Day 113 with baseline, in the ST period, was provided.	Baseline and Day 113.	No
Secondary	Number of Participants Who Died, Experienced SAEs, Experienced AEs or Who Discontinued Due to AEs During the ST Study	AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs or SAEs were recorded.	Continuously through ST period (upto Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first.	Yes
Secondary	Number of Participants Who Experienced Drug-related SAEs and Drug-related AEs During the ST Study	Drug-related AEs are those events with a relationship to the study therapy of certain; probable; possible; or missing. Drug-related SAEs are those events with any relationship to the study therapy.	Continuously through ST period (upto Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first.	Yes
Secondary	Number of Participants With AEs of Special Interest During the ST Study	An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, AEs of particular importance were associated with the use of immunomodulatory agents: infections, autoimmune disorders, malignancies, and injection reaction AEs (systemic AEs occurring within 24 hours of SC injection and local injection site reactions) were recorded.	Continuously through ST period (up to Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first.	Yes
Secondary	Number of Participants With Marked Abnormalities (MAs) in Hematology During the ST Study: Hemoglobin, Hematocrit, Platelet Count, Erythrocytes and Leukocytes	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin: >3 g/dL decrease from pre-treatment (pre Rx); hematocrit: <0.75 * pre-Rx value; platelet count: <0.67 * (LLN -lower limit of normal) (or, if pre-Rx value	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With MAs in Hematology During the ST Study: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute)	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils + bands (absolute): <1.00 * 10^3cells/microlitre (uL); lymphocytes (absolute): <0.75 * 10^3 cells/uL or >7.50 * 10^3 cells/uL; monocytes (absolute): >2.00 * 10^3 cells/uL; basophils (absolute): >0.40 * 10^3 cells/uL; eosinophils (absolute): >0.75 * 10^3 cells/uL.	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With MAs in Serum Chemistry During the ST Study: Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin (Total), G-Glutamyl Transferase (G-GT) and Blood Urea Nitrogen (BUN)	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP: >2.0 * ULN (if pre-Rx > ULN, then >3 * pre-Rx); AST, ALT: > 3 * ULN (if pre-Rx > ULN, then > 4 * pre-Rx); bilirubin (total): >2 * ULN, or if pre Rx > ULN then >4 * Pre Rx; BUN : >2 * pre Rx; GGT : >2 * ULN, or if pre Rx > ULN then >3 * pre Rx.	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With MAs in Serum Chemistry During the ST Study: Creatinine, Sodium (Serum), Potassium (Serum), Chloride (Serum), Calcium (Total) and Protein (Total)	MAs= laboratory measurements marked as abnormal: creatinine: >1.5 * pre-Rx; sodium (serum):<0.95 * LLN or >1.05 * ULN (if pre-Rx < LLN, then <0.95 * pre-Rx or >1.05 * ULN. If pre-Rx > ULN, then >0.95 * pre-Rx or < ULN); potassium (serum):<0.9 * LLN or >1.1 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN; chloride (serum),protein (total):<0.9 * LLN or >1.1 8 ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >1.1 * pre-Rx or < LLN); calcium (total): <0.8 * LLN or >1.2 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >0.75 * pre-Rx or < ULN).	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With MAs in Serum Chemistry During the ST Study: Glucose (Fasting Serum), Albumin, Glucose (Serum), Phosphorous (Inorganic) and Uric Acid	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 * LLN or >1.5 ULN (if pre-Rx	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With MAs in Urinalysis During the ST Study: Protein, Glucose, Blood, Leukocyte Esterase, Red Blood Cells (RBC) and White Blood Cells (WBC)	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs in urinalysis: protein, glucose, blood, leukocyte esterase, RBC, WBC: >= 2+ (or, if value >= 4, or if pre-Rx value = 0 or 0.5, then >= 2x or if pre-Rx value =1, then >= 3, or if pre-Rx = 2 or 3, then >= 4).	Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first.	Yes
Secondary	Number of Participants With Anti-nuclear Antibody (ANA) Category at Day 113 of the ST Study	ANA status was categorized as negative or positive corresponding to the following dilutions: less than 1:160 and greater than equal to 1:160.	Day 113.	Yes
Secondary	Number of Participants With Anti-double Stranded DNA (dsDNA) Category at Day 113 of the ST Study	Anti-dsDNA antibody status was categorized as negative or positive based upon assay-specific numeric cut-off values.	Day 113.	Yes
Secondary	Number of Participants With Clinically Meaningful Vital Signs During the ST Study	Vital signs measurements (including seated blood pressure, heart rate and temperature) were recorded. The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs/physical examination were clinically meaningful.	At screening and on days 1,15,29,43, 57, 85 and 113.	Yes
Secondary	Minimum Plasma Concentration (Cmin) at Each Visit During the 4 Month Treatment Period of the ST Study	Cmin serum abatacept concentration was obtained directly from the concentration-time data.	Days 1, 15, 29, 43, 57, 85 and 113.	No
Secondary	Number of Participants With Abatacept Induced Antibody Responses Over Time During the LTE Study (ECL Method) - All Treated Participants in LTE Study	The Meso-Scale Discovery (MSD) electrochemiluminescence (ECL) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. It is more sensitive and has a higher drug tolerance than ELISA method. For the anti-abatacept antibody ECL (MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10. Antibody responses included CTLA4 and possibly immune globulin (IG), IG and/or junction region.	Days 197, 281, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541, 1625, 1709, 1821, 1989, days post dose: 28, 56, 85, 168	No
Secondary	Change From Baseline in DAS28-CRP Score in the LTE Study - All Treated Participants in LTE Study	DAS28-CRP is a continuous variable which is a composite of 4 variables: the number of tender joints out of 28, the number of swollen joints out of 28, C-reactive protein (CRP) in milligrams/Liter (mg/L) and subject assessment of disease activity measure on a VAS of 100mm. DAS 28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * VAS + 0.96. Baseline was Day 1 of the ST Study; Day 113 was the end of the ST Study.	Baseline, Day 113, Day 1345	No
Secondary	Number of Participants With Clinically Meaningful Improvement From Baseline in the LTE Study - All Treated Participants in LTE Study	A clinically meaningful improvement is defined as a greater than or equal to 1.2 reduction in DAS28-CRP score from baseline. Baseline was Day 1 of the ST Study. Day 113 was the end of the ST Study.	Baseline, Day 113, Day 1345	No
Secondary	Number of Participants in DAS28-CRP Remission and Number of Participants With Low Disease Activity (LDA) in the LTE Study - All Treated Participants in the LTE	DAS28-CRP remission was defined as DAS28-CRP less than 2.6 and LDA was defined as DAS28-CRP less than, equal to 3.2. End of ST Study was Day 113.	Day 113, Day 1345	No
Secondary	Change From Baseline in HAQ-DI in the LTE Study - All Treated Participants in LTE Study	HAQ-DI takes into account participant's use of aids or devices or assistance in scoring algorithm for a disability category. The questionnaire includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The questions are evaluated on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score is calculated by summing worst scores in each domain and dividing by the number of domains answered. Baseline was Day 1 in the ST Study and Day 113 was the last day of the ST Study.	Baseline, Day 113, Day 1345	No
Secondary	Number of Participants With HAQ Responses in the LTE Study - All Treated Participants in the LTE STudy	HAQ response was defined as an improvement of at least 0.3 units from baseline in the HAQ Disability Index (HAQ DI). Baseline was Day 1 of the ST Study and Day 113 was the last day of the ST Study.	Baseline, Day 113, Day 1345	No
Secondary	Number of Participants With Negative Status for RF up to 7 Days After Last Dose of Abatacept in the LTE Period - All Treated Participants in LTE Study	RF is an autoantibody that is usually present in the serum of people with rheumatoid arthritis. The cut-point value for seroconversion was 15 IU/mL (>= 15 IU/mL resulted in a positive result).	Continuously from start of LTE period up to 7 days post the last dose	No
Secondary	Change From Baseline in DAS28-CRP Score and Physical Function (HAQ-DI) Score in the LTE Study - Abatacept Monotherapy Subgroup	Abatacept Monotherapy Subgroup consisted of participants who received SC abatacept and did not receive MTX in the ST and LTE Studies. DAS28-CRP: continuous variable which is a composite of 4 variables:number of tender joints out of 28, number of swollen joints out of 28, C-reactive protein (CRP) in mg/L and self assessment of disease activity measure on a VAS of 100mm. DAS 28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * VAS + 0.96. HAQ-DI includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score sums worst scores in each domain and divides by the number of domains answered. Baseline was Day 1 of Short Term Study. Day 113 was the last day of the Short Term Study.	Baseline, Day 113, Day 1345	No
Secondary	Number of Participants in DAS 28-CRP Remission and Low Disease Activity (LDA) in the LTE Study - Abatacept Monotherapy Subgroup	Remission was defined as DAS 28-CRP < 2.6 and LDA was defined as DAS 28-CRP <= 3.2. End of ST Study was Day 113. Abatacept Monotherapy Subgroup was defined as those participants who received as at least 1 dose of abatacept and did not receive MTX in the ST and LTE Studies.	Day 113, Day 1345	No
Secondary	Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs), or Discontinued Due to AEs and/or SAEs During the LTE Period - All Treated Participants in LTE Study	AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Drug-related AEs/SAEs are those events with a relationship to the study therapy of certain; probable; possible; or missing.	Continuously from start of LTE Study up to 56 days post the last dose	Yes
Secondary	Number of Participants With AEs of Special Interest During the LTE Study - All Treated Participants in LTE Study	An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, AEs of particular importance were associated with the use of immunomodulatory agents: infections, autoimmune disorders, malignancies, and injection reaction AEs (systemic AEs occurring within 24 hours of SC injection and local injection site reactions) were recorded.	Continuously from start of LTE Study up to 56 days post the last dose	Yes
Secondary	Number of Participants With Marked Abnormalities (MAs) in Hematology During the LTE Period - All Treated Participants in LTE Study	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin: >3 g/dL decrease from pre-treatment (pre Rx); hematocrit: <0.75 * pre-Rx value; platelet count: <0.67 * (LLN -lower limit of normal) (or, if pre-Rx value	Continuously from start of LTE Study up to 56 days post the last dose	Yes
Secondary	Number of Participants With MAs in Serum Chemistry (Liver and Kidney Function) During the LTE Period - All Treated Participants in LTE Study	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin (Total), G-Glutamyl Transferase (G-GT), Blood Urea Nitrogen (BUN) and Creatinine MA criteria: ALP: >2.0 * ULN (if pre-Rx > ULN, then >3 * pre-Rx); AST, ALT: > 3 * ULN (if pre-Rx > ULN, then > 4 * pre-Rx); bilirubin (total): >2 * ULN, or if pre Rx > ULN then >4 * Pre Rx; BUN : >2 * pre Rx; GGT : >2 * ULN, or if pre Rx > ULN then >3 * pre Rx; creatinine: >1.5 * pre-Rx.	Continuously from start of LTE Study up to 56 days post the last dose	Yes
Secondary	Number of Participants With MAs in Serum Chemistry (Electrolytes, Glucose, Protein, and Metabolite) During the LTE Period - All Treated Participants in LTE Study	Sodium (serum):<0.95 * LLN or >1.05 * ULN (if pre-Rx < LLN, then <0.95 * pre-Rx or >1.05 * ULN. If pre-Rx > ULN, then >0.95 * pre-Rx or < ULN); potassium (serum):<0.9 * LLN or >1.1 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN; chloride (serum),protein (total):<0.9 * LLN or >1.1 8 ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >1.1 * pre-Rx or < LLN); calcium (total): <0.8 * LLN or >1.2 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >0.75 * pre-Rx or < ULN); phosphorous (inorganic):<0.75 * LLN or >1.25 * ULN (if pre-Rx < ULN, then <0.67 * pre-Rx or < ULN. If pre-Rx > ULN, then >1.33 * re-Rx or	Continuously from start of LTE Study up to 56 days post the last dose	Yes
Secondary	Number of Participants With MAs in Urinalysis During the LTE Period: Protein, Glucose, Blood, Leukocyte Esterase, Red Blood Cells (RBC) and White Blood Cells (WBC) - All Treated Participants in LTE Study	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs in urinalysis: protein, glucose, blood, leukocyte esterase, RBC, WBC: >= 2+ (or, if value >= 4, or if pre-Rx value = 0 or 0.5, then >= 2x or if pre-Rx value =1, then >= 3, or if pre-Rx = 2 or 3, then >= 4).	Continuously from start of LTE Study up to 56 days post the last dose	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm