Study to Assess Steady-State Trough Concentrations, Safety, and Immunogenicity of Abatacept After Subcutaneous (SC) Administration to Subjects With Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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The purpose of this study is to study serum levels of Abatacept after subcutaneous dosing in subjects with RA.

Official Title
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A Study to Assess the Steady-State Trough Serum Concentration, Safety, and Immunogenicity of Abatacept (BMS-188667) Administered Subcutaneously in Subjects With Active Rheumatoid Arthritis Who Are Receiving Disease Modifying Ant-Rheumatic Drugs (DMARDs)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Abatacept or Placebo (both as IV & SC Solution)
* Drug: Abatacept or Placebo (both as IV & SC Solution)
* Drug: Abatacept or Placebo (both as IV & SC solution)
* Drug: Abatacept or Placebo (both as IV & SC solution)
* Drug: Abatacept or Placebo (both as IV & SC solution)
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet ARA criteria for diagnosis of RA with active disease. RA diagnosis for at least 1 year. > = 6 swollen joints. > = 8 tender joints. Taking methotrexate (MTX) or MTX plus not more than 1 added oral DMARD for > = 3 months and stable for 28 days prior to dosing. Exclusion Criteria: Serious acute or bacterial infection in last 3 months. Chronic or recurrent bacterial infections. History of TB within previous 3 years or old TB not adequately treated. Specific lab test abnormalities History of cancer within 5 years. Exposure to CTLA4Ig (Cytotoxic T-lymphocyte (T-cell)-associated antigen 4Ig), belatacept, rituximab, efalizumab, alefacept, or other investigational drug or biologic. Treatment with hydroxychloroquine, azathioprine, leflunomide, immunoadsorption columns, mycophenolate mofetil, cyclosporine, D-Penicillamine or calcineurin inhibitors. Exposure to live vaccines.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1 (weight < 60 kg)<br> | Drug: Abatacept or Placebo (both as IV & SC Solution)<br>* Abatacept & Placebo as IV & SC solution, IV/SC, Abatacept 500 mg IV (Day 1)/Abatacept 75 mg SC (once weekly for 12 weeks) or Placebo IV(Day 1)/Placebo SC (once weekly for 12 weeks), 12 weeks then long term extension (LTE).<br>* Other names: Orencia;|
| Placebo Comparator: Group 2 (weight < 60 kg)<br> | Drug: Abatacept or Placebo (both as IV & SC Solution)<br>* Abatacept & Placebo as IV & SC solution, IV/SC, Abatacept 500 mg IV (Day 1)/Abatacept 125 mg SC (once weekly for 12 weeks) or Placebo IV(Day 1)/Placebo SC (once weekly for 12 weeks), 12 weeks then long term extension (LTE).<br>* Other names: Orencia;|
| Placebo Comparator: Group 3 (weight 60-100 kg)<br> | Drug: Abatacept or Placebo (both as IV & SC solution)<br>* Abatacept & Placebo as IV & SC solution, IV/SC, Abatacept 750 mg IV (Day 1)/Abatacept 125 mg SC (once weekly for 12 weeks) or Placebo IV(Day 1)/Placebo SC (once weekly for 12 weeks), 12 weeks then long term extension (LTE).<br>* Other names: Orencia;|
| Placebo Comparator: Group 4 (weight > 100 kg)<br> | Drug: Abatacept or Placebo (both as IV & SC solution)<br>* Abatacept & Placebo as IV & SC solution, IV/SC, Abatacept 1000 mg IV (Day 1)/Abatacept 125 mg SC (once weekly for 12 weeks) or Placebo IV(Day 1)/Placebo SC (once weekly for 12 weeks), 12 weeks then long term extension (LTE).<br>* Other names: Orencia;|
| Placebo Comparator: Group 5 (weight > 100 kg)<br> | Drug: Abatacept or Placebo (both as IV & SC solution)<br>* Abatacept & Placebo as IV & SC solution, IV/SC, Abatacept 1000 mg IV (Day 1)/Abatacept 200 mg SC (once weekly for 12 weeks) or Placebo IV(Day 1)/Placebo SC (once weekly for 12 weeks), 12 weeks then long term extension (LTE).<br>* Other names: Orencia;|
| Experimental: Abatacept<br>Long Term | Drug: Abatacept<br>* Solution in pre-filled syringes, Subcutaneously, 125 mg, Weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short Term Period: Steady-state Trough Serum Concentration (Cmin) of Abatacept Following Weekly Subcutaneous Dosing in Participants With Active Rheumatoid Arthritis Receiving Disease Modifying Anti-rheumatic Drugs (DMARDS) | Participants received abatacept while also receiving DMARDS over a short term (ST) 12 Week period. To eliminate contribution from the IV loading dose of abatacept during the short term study period, Cmin values were selected from Days 71 to 85, when contribution from IV was negligible. Minimum trough serum concentration of abatacept (Cmin) was measured in micrograms/milliliter (µg/mL). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Days 71 to 85 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Discontinuations Due to Adverse Events Reported During the Variable Dosing Phase of the Long Term Period (LTE) | AEs during variable dose phase of LTE + 56 days post last dose in the variable dose phase or start of the fixed dose phase, which ever came first; includes deaths reported during the variable dose phase including those that occurred greater than 56 days after last dose. Medical Dictionary for Regulatory Activities (MedDRA) version: 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization (included hospitalizations for elective surgical procedures). Treatment-related=having certain, probable, possible, or missing relationship to study drug. Data presented by treatment the participant was randomized to and not what they actually received. | Day 85 to 56 days post last dose | 
| Number of Participants With Pre-specified AEs of Special Interest in the Variable Dosing Phase of Long Term Extension (LTE) | LTE period with variable abatacept dosing starting on Day 85 and continuing until Day 533 when LTE fixed dosing started. AEs of special interest: infection and/or infestation; neoplasms (malignant); pre-specified autoimmune disorder; infusional AEs (peri-infusional: pre-specified AEs occurring during first 24 hours (hrs) after start of the IV loading dose; acute infusional: pre-specified AEs occurring during the first hour after the start of the IV loading dose; systemic injection site reactions (SIR): pre-specified AEs for SIR; local injection site reaction: pre-specified AEs for local site reaction. Data are presented by treatment the participant was randomized to and not what they actually received. | Day 85 to Day 533 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Discontinuations Due to Adverse Events Summarized Over the Entire Long Term Extension (LTE) Period (Both Variable and Fixed Dosing) | On Day 85 participants rolled over into the LTE with variable dose phase first and at Day 533, a fixed dose phase of 125 mg abatacept SC weekly, irrespective of body weight. This summary includes AEs reported during entire LTE treatment plus 56 days post last dose; includes all deaths reported during the LTE including those that occurred greater than 56 days after last dose. MedDRA version: 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization (also included hospitalizations for elective surgical procedures). Treatment-related=having certain, probable, possible, or missing relationship to study drug. | Day 533 to 56 Days Post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short Term Period: Peak Serum Concentration (Cmax) of Abatacept at Steady State in Participants With Rheumatoid Arthritis Receiving DMARDS | Peak serum concentration (Cmax) of abatacept after weekly SC administration was determined between the SC dosing interval from Day 71 to 78. Abatacept in human serum was measured by enzyme-linked immunosorbent assay (ELISA). Lower limit of quantification (LLOQ) was 0.001, Upper limit of quantification (ULOQ) was 0.030. Cmax measured in micrograms per milliliter(µg/mL). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 71 to Day 78 | 
| Short Term Period: Area Under the Curve (AUC) in Time Interval of 7 Days [AUC(TAU)] of Abatacept in Participants With Rheumatoid Arthritis Receiving DMARDS | The steady-state pharmacokinetic parameter AUC(TAU) of abatacept after weekly SC administration was determined between the SC dosing interval from Day 71 to 78 (TAU=7 days). Abatacept in human serum was measured by enzyme-linked immunosorbent assay (ELISA). Lower limit of quantification (LLOQ) was 0.001; Upper limit of quantification (ULOQ) was 0.030. AUC(TAU) measured in in micrograms*hours per milliliter (µg*h/mL). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 71 to Day 78 | 
| Short Term Period: Summary of Adverse Events (AEs), Serious AEs, Deaths, and Discontinuations Due to AEs During 12 Weeks of Treatment With Either Abatacept or Placebo | Number of Participants with Adverse events (AEs), Serious AEs, discontinuations due to AEs, or Deaths occurring while participant was on treatment from Day 1 (treatment) to Day 85 or early termination from the study. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization (also included hospitalizations for elective surgical procedures). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Number of Participants With Pre-specified Adverse Events (AEs) of Special Interest After Administration of Abatacept or Placebo Over 12 Weeks | AEs of special interest: infection and/or infestation; neoplasms (benign, malignant, unspecified; autoimmune disorder; infusional AEs (peri-infusional: AEs occurring during first 24 hours (hrs) after start of the IV loading dose; acute infusional: AEs occurring during the first hour after the start of the IV loading dose; injection site AEs: AEs occurring at the site of the SC injection. Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Mean Percent Change From Baseline on Day 85 in Participants Positive for Serum Rheumatoid Factor During Abatacept or Placebo Administration | Serum samples were obtained on Days 1, 8, 15, 29, 57 and day of discharge (Day 85 or earlier) for determination of presence of rheumatoid factor (RF). Baseline was defined as Day 1 to calculate percent change. Lower limit of quantitation (LLQ) was 5 Units/milliliter (U/mL). Values below LLQ were set to 2.5 U/mL. Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Number of Participants With Laboratory Abnormalities in Hematology at Baseline (Day 1) to End of Period (Day 85) | Blood samples were obtained: At screening, within 24 hours prior to study drug administration on Day 1, on Days 15, 29, 57 and at study discharge. Baseline (BL) defined as Day 1 prior to treatment. Common toxicity criteria (CTC), Version 3 used to assess parameters. lower limit of normal (LLN). ANC=absolute neutrophil count. White blood cells Grade (Gr) 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L. ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L. Lymphocytes Gr 1: <LLN to 3.0, Gr 2: 2.0 < 3.0, Gr 3: 1.0 to < 2.0, Gr 4; < 1.0. Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L. Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. Hematocrit (%): <0.75*pre-treatment. Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Number of Participants With Laboratory Abnormalities in Serum Chemistry at Baseline and on Treatment up to Day 85 | Screening, BL, Days 15, 29, 57, 85 or discharge. Upper limit of normal (ULN). CTC grade (Gr): Alanine transaminase Gr 1:>ULN to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. Aspartate aminotransferase Gr 1: >ULN to 2.5*ULN; Gr 2:>2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. G-Glutamyl Transferase (U/L) Gr 1:>ULN to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. Alkaline phosphatase (U/L) Gr 1:>ULN to 2.5*ULN, Gr2:>2.5 to 5.0*ULN, Gr3:>5.0 to 20.0*ULN, Gr4: >20.0*ULN; creatinine (mg/dL) Gr 1: >ULN to 1.5*ULN; Gr 2: >1.5 to 3.0*ULN; Gr 3: >3.0 to 6.0*ULN; Gr 4: >10.0*ULN. Albumin (g/dL) Gr 1:<LLN to 3.0; Gr 2:<3.0 to 2.0; Gr 3: <2.0. Uric Acid (mg/dL)Gr 1: >1.0 x ULN to 10.0; Gr 4: >10.0. Sodium (mEq/L) Gr 1: >ULN to 150; Gr 2: >150 to 155; Gr 3: >155 to 160; Gr 4: > 160. Potassium (mEq/L) Gr 1: >ULN to 5.5; Gr 2: >5.5 to 6.0; Gr 3: >6.0 to 7.0; Gr 4: >7.0. Data presented by treatment participant actually received. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Mean Change From Baseline at Day 85 in Blood Pressure After SC Administration of Abatacept or Placebo in Participants With Rheumatoid Arthritis Receiving DMARDS | Blood pressure (systolic and diastolic) was recorded while the participant was seated during the screening visit, at baseline on Day 1 (prior to administration of IV infusion), prior to administration of all SC injections, and at study discharge (Day 85 or 7 days after the last dose for subjects who terminated early). In addition, blood pressure was recorded at 30 and 60 minutes after the start of the IV infusion on Day 1, and 30 and 60 minutes after all SC injections. Blood pressure was measured in millimeters of mercury (mm Hg). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Mean Change From Baseline at Day 85 in Pulse Rate After SC Administration of Abatacept or Placebo in Participants With Rheumatoid Arthritis Receiving DMARDS | Pulse rate was taken while participant was seated. Pulse rate was recorded during the screening visit, at baseline on Day 1 (prior to administration of IV infusion), prior to administration of all SC injections, and at study discharge (Day 85 or 7 days after the last dose for subjects who terminated early). In addition, vital signs were recorded at 30 and 60 minutes after the start of the IV infusion on Day 1, and 30 and 60 minutes after all SC injections. Pulse rate measured in beats/min (bpm). Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Day 1 to Day 85 (or early termination) | 
| Short Term Period: Mean Change From Screening to Day 85 in Electrocardiogram (QT, PR Intervals, QRS Width) After SC Administration of Abatacept or Placebo in Participants With Rheumatoid Arthritis Receiving DMARDS | A 12-lead electrocardiogram (ECG) was recorded at screening and at discharge from the study (Day 85 or 7 days after the last dose of study drug for those subjects who terminated early). If there was no history of known cardiac events, an ECG was performed within 6 months of study entry, and documentation was on file, then the screening ECG was not repeated at screening. QT interval, PR interval and QRW Width were reported in milliseconds (msec). If no ECG issues were found in the 12 weeks of the Short Term Period, ECG was not repeated during LTE. Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Screening to Day 85 (or early termination) | 
| Short Term Period: Mean Change From Screening at Day 85 in ECG (Heart Rate) After SC Administration of Abatacept or Placebo in Participants With Rheumatoid Arthritis Receiving DMARDS | A 12-lead electrocardiogram (ECG) was recorded at screening and at discharge from the study (Day 85 or 7 days after the last dose of study drug for those subjects who terminated early). If there was no history of known cardiac events, an ECG was performed within 6 months of study entry, and documentation was on file, then the screening ECG was not repeated at screening. Heart Rate was reported in beats per minute (bpm). In no ECG issues were found in the 12 weeks of the Short Term Period, ECG was not repeated during LTE. Data are presented by treatment the participant actually received, not by what they were randomized to receive. | Screening to Day 85 (or early termination) | 
| Overall Study ST and LTE Periods: Number of Participants With Anti-abatacept Antibodies and/or Anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Antibodies | Assessment of positive antibody response based upon analysis using a validated enzyme-linked immunosorbent assay (ELISA) with a cut-off value. CTLA4 is a protein receptor that downregulates the immune system. Short Term (ST) period was initial 12 Weeks of the study. Overall LTE includes both the variable and fixed abatacept dosing periods and was from the end of the ST period (Day 85) up to 168 days post last dose (treatment in LTE ranged from 4.4 to 74.2 months. Data in the ST period are summarized by the treatment the participants actually received, while the LT period data are summarized by treatment the participant was randomized to receive. | ST: Day 1 to Day 85; LTE: Day 85 to 168 days post last dose |