Methotrexate-Inadequate Response Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether a weekly subcutaneous dose of abatacept yields clinical efficacy comparable to that of monthly intravenous doses of abatacept in participants with rheumatoid arthritis and an inadequate response to current methotrexate therapy.

Official Title
-----------------
A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects With Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate

Conditions
-----------------
Rheumatoid Arthritis (RA)

Intervention / Treatment
-----------------
* Drug: Subcutaneous (SC) Abatacept
* Drug: Intravenous (IV) Abatacept


Participation Criteria
=================
Eligibility Criteria
-----------------
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Subjects who are considered methotrexate inadequate responders 10 or more swollen joints (66 joint count) and 12 or more tender joints (68 joint count) Exclusion Criteria: Subjects who failed one or multiple anti-tumor necrosis factor (TNF) therapies Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus erythematous) Subjects with active vasculitis of a major organ system (except for subcutaneous rheumatoid nodules) Subjects with severe chronic or recurrent bacterial infections Subjects who have received treatment with rituximab An Anti-TNF Failure Sub-study was initiated (recruited separately from Main study) using the same treatment as the Main study in order to assess the immunogenicity and safety in the Anti-TNF Failure population. The Sub-study terminated due to low recruitment and participants were permitted to roll into the LT Open Label Period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subcutaneous (SC) Abatacept<br>Participants received 125 mg weekly SC abatacept injections (with an intravenous [IV] abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. | Drug: Subcutaneous (SC) Abatacept<br>* Participants received 125 mg weekly SC abatacept injections (with an intravenous [IV] abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment.<br>* Other names: BMS-188667;|
| Active Comparator: Intravenous (IV) Abatacept<br>Participants received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter. A double-dummy design was used to protect the blind, thus, participants also received SC injections of placebo (SC Placebo). | Drug: Intravenous (IV) Abatacept<br>* Participants received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter. A double-dummy design was used to protect the blind, thus, participants also received SC injections of placebo (SC Placebo). 500mg (for body weight up to 60 kg) 750 mg (body weight between 61 and 100 kg) 1g (body weight above 100 kg)infusions<br>* Other names: BMS-188667;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Period: Number of Participants Achieving American College of Rheumatology (ACR) 20 Response at Day 169 | The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein). | Day 169 | 
| Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population | Serum samples from all treated adult participants with active rheumatoid arthritis who were from the Anti-TNF failure population were screened for the presence of drug-specific antibodies using Enzyme Linked Immunoabsorbant Assay (ELISA). The number of participants who had the presence of anti-abatacept antibodies or anti-CTLA-4 antibodies present in their serum are summarized. | Days 85, and 169 and postvisits on Days 28, 56, and 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Period: Number of Participants Achieving ACR 50 and ACR 70 Responses at Day 169 | The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. | Day 169 | 
| Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Participants With Assessments at Day 169 | The disability section of the full HAQ-DI includes 20 questions to assess physical functions 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=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. | Day 169 | 
| Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI | The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI ranges from 0 to a maximum overall score of 3.0. | Baseline to Day 169 | 
| Double-blind Period: Number of Participants Achieving Clinically Meaningful HAQ-DI Response at Day 169 | The disability section of the full HAQ-DI includes 20 questions to assess physical functions 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=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ-DI response=an improvement of at least 0.3 units from baseline in HAQ-DI. | Day 169 | 
| Double-blind Period: Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation | AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug | Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first. | 
| Anti-TNF Failure Sub-study Double-blind Period: Number of Participants With SAEs, AEs Leading to Discontinuation or Who Died | AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. | Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first. | 
| Double-blind Period: Number of Participants With AEs of Special Interest | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections,serious infections,and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (prespecified AEs occurring within 1 hr of start of infusion), peri-infusional AEs (prespecified AEs occurring within 24 hrs of the start of infusion), system injection reactions, and local injection site reactions | Day 1 up to 56 days post last dose in short- term period or first dose in the long -term period, whichever occurs first. | 
| Double-blind Period: Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements | Vital sign measurements were performed for participants before and after infusion/subcutaneous injection of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. | Day 1 through end of short-term period (Day 169) | 
| Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality | ULN=upper limit of normal; LLN=lower limit of normal; BL= baseline. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL; hematocrit: <0.75*BL; erythrocytes: <0.75*BL; platelets: <0.67*LLN/>1.5*ULN, or if BL<LLN, use <0.5*BL and <100,000 mm^3; leukocytes: <0.75*LLN/>1.25*ULN, or if BL<LLN use <0.8*BL or >ULN, or if BL>ULN, use >1.2*BL or <LLN; neutrophils+bands: <1.0*10^3 c/uL; eosinophils: >0.750*10^3 c/uL; basophils: >400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750*10^3 c/uL/>7.50*10^3 c/uL. | Day 1 through end of short-term period (Day 169) | 
| Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality | Marked abnormality criteria: Alkaline phosphatase (ALP): >2*ULN, or if BL>ULN, use >3*BL; aspartate aminotransferase (AST): >3*ULN, or if BL>ULN, use >4*BL; alanine aminotransferase (ALT): >3*ULN, or if BL>ULN, use >4*BL; G-glutamyl transferase (GGT): >2* ULN, or if BL>ULN, use >3*BL; bilirubin: >2* ULN, or if BL>ULN, use >4*BL; blood urea nitrogen: >2* BL; creatinine: >1.5*BL | Day 1 through end of short-term period (Day 169) | 
| Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality | Marked abnormality criteria: Sodium: <0.95*LLN/>1.05*ULN, or if BL<LLN, use <0.95* BL or >ULN, or if BL>ULN, use>1.05* BL or <LLN; potassium: <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN, use>1.1* BL or <LLN; chlorine: <0.9*LLN/>1.1* ULN, or if BL<LLN, use <0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN; calcium: <0.8* LLN/>1.2* ULN, or if BL<LLN, use <0.75*BL or >ULN, or if BL>ULN, use>1.25* BL or <LLN; phosphorous: <0.75* LLN/>1.25*ULN, or if BL<LLN, use 0.67*BL or >ULN, or if BL>ULN, use>1.33* BL or <LLN | Day 1 through end of short-term period (Day 169) | 
| Double-blind Period: Minimum Observed Serum Concentration of Abatacept |  | Days 57, 85, 113, 120, 127, 134, 141, and 169 | 
| Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept | Serum concentrations of abatacept were analyzed using a validated ELISA. Steady-state trough observed concentration in serum (Cminss) was measured in μg/mL. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. | Days 57, 85, 113, 120, 127, 134, 141, and 169 (ST Period) | 
| Double-blind Period: Maximum Observed Serum Concentration of Abatacept |  | End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous | 
| Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept | Serum concentrations of abatacept were analyzed using a validated enzyme-linked immunosorbent assay (ELISA). Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Cmax was measured in micrograms per milliliter (μg/mL). | End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous | 
| Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept |  | Dosing interval between Days 113 and 141 (TAU=28 days) | 
| Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept | Serum concentrations of abatacept were analyzed using a validated ELISA. AUC(TAU) was measured as μg*h/mL. Samples for AUC (TAU) were obtained on Days 113, 120, 127, 134, and 141. | Dosing Interval between Days 113 and 141 (TAU=28 days) | 
| Double-blind Period: Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA) | Serum samples from all treated adult participants with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept (anti-ABA) or anti-CTLA4 antibody (anti-CTLA4). | Days 85, and 169 and postvisits on Days 28, 56, and 85 | 
| Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period | C-reactive protein is an acute phase reactant protein that is a clinical marker for rheumatoid arthritis. Time-matched median percent change from baseline= (time-matched baseline value - Post-baseline value)/time-matched baseline value*100, where the time-matched baseline value represents the median baseline value for only that cohort of participants with measurements available at that visit. | Baseline to Days 15, 29, 57, 85, 113, 141, and 169 | 
| Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized | An electrochemiluminescence immunoassay screened sera for drug-specific antibodies, immunocompetition was used to identify specific anti-abatacept reactivity. CTLA4 and Possibly Ig category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; abatacept molecule). Ig and/or Junction (JNCT) category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a postbaseline titer higher than Baseline, or any postbaseline positivity if Baseline value was missing. Trt=treatment. | Days 85, and 169 and postvisits on Days 28, 56, and 85 | 
| Double-blind Period: Number of Participants Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline | Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process. | Baseline to Day 169 | 
| Open-Label LT Period: Number of Participants Achieving ACR 20 Response at Days 169, 729, 1261, and 1821 | The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein). | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Number of Participants Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821 | The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821 | The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from very good to very bad). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. A clinically significant response= decrease in DAS28 score of >1.2 from baseline. | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Number of Participants Achieving DAS 28 Remission at Days 169, 729, 1261, 1821 | The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from very good to very bad). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Number of Participants Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821 | The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from very good to very bad). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Number of Participants With HAQ-DI Response at Days 169, 729, 1261, 1821 | The disability section of the full HAQ includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0. HAQ response was defined as an improvement (reduction) from baseline (Day 1) of at least 0.3 units in the HAQ score. | Days 169, 729, 1261, 1821 | 
| Open-Label LT Period: Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation | AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug | End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014) | 
| Open-Label LT Period: Number of Participants With AEs of Special Interest | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections, serious infections, and opportunistic infections; autoimmune disorders; malignancies; system injection reactions, and local injection site reactions. | End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014) | 
| Open-Label LT Period: Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements | Vital sign assessments were performed in the LT period at 12-week intervals and at a yearly visit (at 16-week intervals) and, for participants who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Vital signs included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. | End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014) | 
| Open-Label LT Period: Number of Participants With Clinically Significant Laboratory Abnormalities | Laboratory assessments were performed in the LT period at 12-week intervals and at a yearly visit and, for participants who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Abnormalities were determined to be clinically significant by the investigator. | End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014) |