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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00547521

Registration number

NCT00547521

Ethics application status

Date submitted

19/10/2007

Date registered

22/10/2007

Date last updated

23/03/2015

Titles & IDs

Public title

Phase IIIB Subcutaneous Abatacept Monotherapy Study

Scientific 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

Secondary ID [1]

IM101-173

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Rheumatoid Arthritis (RA)

Condition category

Condition code

Musculoskeletal

Osteoarthritis

Inflammatory and Immune System

Rheumatoid arthritis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - abatacept
Treatment: Drugs - Methotrexate (MTX)

Experimental: Subcutaneous (SC) Abatacept + Methotrexate (MTX) Cohort - In the ST period, participants were administered a dose of 125 mg abatacept SC, once weekly, for 4 months. Participants were also administered a stable MTX dose of greater than or equal to 10 mg once weekly for at least 4 weeks prior to first injection of SC abatacept.

Experimental: SC Abatacept Monotherapy Cohort - In the ST period, participants were administered a dose of 125 mg abatacept SC, once weekly, for 4 months. Participants did not receive MTX at screening i.e., MTX naive, or discontinued MTX due to lack of efficacy or tolerability at least 4 weeks prior to first injection of SC abatacept.

Treatment: Drugs: abatacept
solution, subcutaneous injection, 125 mg/kg, weekly, 106 days in short term; long term is open

Treatment: Drugs: Methotrexate (MTX)
Participants who were currently receiving methotrexate at a stable dose = 10 mg for at least 4 weeks

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (Enzyme-linked Immunosorbent Assay [ELISA] Method) at Day 113 of the ST Study

Assessment method [1]

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.

Timepoint [1]

Day 113

Primary outcome [2]

Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (ELISA Method) Over Time During the ST Study

Assessment method [2]

Timepoint [2]

Day 15, 29, 43, 57, 85,113 and 28, 56, and 85 days post last dose.

Primary outcome [3]

Number of Participants With Positive Anti-abatacept Responses to Abatacept (Meso-Scale Discovery [MSD] Electrochemiluminescence [ECL] Assay Method) Over Time During the ST Study

Assessment method [3]

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.

Timepoint [3]

Day 15, 29, 43, 57, 85,113 and 28, 56 and 85 days post last dose.

Primary outcome [4]

Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for ELISA Results)

Assessment method [4]

Timepoint [4]

Day 113.

Primary outcome [5]

Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for MSD Results)

Assessment method [5]

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.

Timepoint [5]

Day 113.

Primary outcome [6]

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)

Assessment method [6]

Timepoint [6]

Baseline and on day 15, 29, 43, 57, 85 and 113

Primary outcome [7]

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)

Assessment method [7]

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.

Timepoint [7]

Baseline and day 15, 29, 43, 57, 85 and 113.

Secondary outcome [1]

Change From Baseline in DAS28-CRP Score at End of 4-month (Day 113) of the ST Study

Assessment method [1]

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.

Timepoint [1]

Baseline and Month 4 (Day113).

Secondary outcome [2]

Number of Participants With Clinically Meaningful Improvement at End of 4-month (Day 113) of the ST Study

Assessment method [2]

A clinically meaningful improvement is defined as a greater than or equal to 1.2 reduction in DAS28-CRP score from baseline.

Timepoint [2]

Day 113.

Secondary outcome [3]

Change From Baseline in Physical Functioning (HAQ-DI) at End of the 4-month Treatment Period (Day 113) of the ST Study

Assessment method [3]

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.

Timepoint [3]

Baseline and Month 4 (Day 113).

Secondary outcome [4]

Change From Baseline in All HAQ-DI Components at End of the 4-month Treatment Period (Day 113) of the ST Study

Assessment method [4]

Timepoint [4]

Baseline and Month 4 (Day113).

Secondary outcome [5]

Cross Tabulations of Number of Participants With Positive and Negative Status for RF at Day 113 With Baseline, in the ST Study

Assessment method [5]

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.

Timepoint [5]

Baseline and Day 113.

Secondary outcome [6]

Number of Participants Who Died, Experienced SAEs, Experienced AEs or Who Discontinued Due to AEs During the ST Study

Assessment method [6]

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.

Timepoint [6]

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.

Secondary outcome [7]

Number of Participants Who Experienced Drug-related SAEs and Drug-related AEs During the ST Study

Assessment method [7]

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.

Timepoint [7]

Secondary outcome [8]

Number of Participants With AEs of Special Interest During the ST Study

Assessment method [8]

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.

Timepoint [8]

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.

Secondary outcome [9]

Number of Participants With Marked Abnormalities (MAs) in Hematology During the ST Study: Hemoglobin, Hematocrit, Platelet Count, Erythrocytes and Leukocytes

Assessment method [9]

Timepoint [9]

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.

Secondary outcome [10]

Number of Participants With MAs in Hematology During the ST Study: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute)

Assessment method [10]

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.

Timepoint [10]

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.

Secondary outcome [11]

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)

Assessment method [11]

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.

Timepoint [11]

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.

Secondary outcome [12]

Number of Participants With MAs in Serum Chemistry During the ST Study: Creatinine, Sodium (Serum), Potassium (Serum), Chloride (Serum), Calcium (Total) and Protein (Total)

Assessment method [12]

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).

Timepoint [12]

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.

Secondary outcome [13]

Number of Participants With MAs in Serum Chemistry During the ST Study: Glucose (Fasting Serum), Albumin, Glucose (Serum), Phosphorous (Inorganic) and Uric Acid

Assessment method [13]

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 \ULN; albumin: \<0.9 \* LLN (if pre-Rx \< LLN, then \<0.75 \* pre-Rx); uric acid: \>1.5 \* ULN (if pre-Rx \> ULN, then \>2.0 \* pre-Rx); 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 \< LLN); glucose (serum): \<65 mg/dL or \>220 mg/dL.

Timepoint [13]

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.

Secondary outcome [14]

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)

Assessment method [14]

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).

Timepoint [14]

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.

Secondary outcome [15]

Number of Participants With Anti-nuclear Antibody (ANA) Category at Day 113 of the ST Study

Assessment method [15]

ANA status was categorized as negative or positive corresponding to the following dilutions: less than 1:160 and greater than equal to 1:160.

Timepoint [15]

Day 113.

Secondary outcome [16]

Number of Participants With Anti-double Stranded DNA (dsDNA) Category at Day 113 of the ST Study

Assessment method [16]

Anti-dsDNA antibody status was categorized as negative or positive based upon assay-specific numeric cut-off values.

Timepoint [16]

Day 113.

Secondary outcome [17]

Number of Participants With Clinically Meaningful Vital Signs During the ST Study

Assessment method [17]

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.

Timepoint [17]

At screening and on days 1,15,29,43, 57, 85 and 113.

Secondary outcome [18]

Minimum Plasma Concentration (Cmin) at Each Visit During the 4 Month Treatment Period of the ST Study

Assessment method [18]

Cmin serum abatacept concentration was obtained directly from the concentration-time data.

Timepoint [18]

Days 1, 15, 29, 43, 57, 85 and 113.

Secondary outcome [19]

Number of Participants With Abatacept Induced Antibody Responses Over Time During the LTE Study (ECL Method) - All Treated Participants in LTE Study

Assessment method [19]

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.

Timepoint [19]

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

Secondary outcome [20]

Change From Baseline in DAS28-CRP Score in the LTE Study - All Treated Participants in LTE Study

Assessment method [20]

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.

Timepoint [20]

Baseline, Day 113, Day 1345

Secondary outcome [21]

Number of Participants With Clinically Meaningful Improvement From Baseline in the LTE Study - All Treated Participants in LTE Study

Assessment method [21]

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.

Timepoint [21]

Baseline, Day 113, Day 1345

Secondary outcome [22]

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

Assessment method [22]

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.

Timepoint [22]

Day 113, Day 1345

Secondary outcome [23]

Change From Baseline in HAQ-DI in the LTE Study - All Treated Participants in LTE Study

Assessment method [23]

Timepoint [23]

Baseline, Day 113, Day 1345

Secondary outcome [24]

Number of Participants With HAQ Responses in the LTE Study - All Treated Participants in the LTE STudy

Assessment method [24]

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.

Timepoint [24]

Baseline, Day 113, Day 1345

Secondary outcome [25]

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

Assessment method [25]

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).

Timepoint [25]

Continuously from start of LTE period up to 7 days post the last dose

Secondary outcome [26]

Change From Baseline in DAS28-CRP Score and Physical Function (HAQ-DI) Score in the LTE Study - Abatacept Monotherapy Subgroup

Assessment method [26]

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.

Timepoint [26]

Baseline, Day 113, Day 1345

Secondary outcome [27]

Number of Participants in DAS 28-CRP Remission and Low Disease Activity (LDA) in the LTE Study - Abatacept Monotherapy Subgroup

Assessment method [27]

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.

Timepoint [27]

Day 113, Day 1345

Secondary outcome [28]

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

Assessment method [28]

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.

Timepoint [28]