Phase IIIB Switching From Intravenous to Subcutaneous Study

Study Overview
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Brief Summary
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The purpose of this study is to determine whether switching to subcutaneous administration of abatacept will be safe in participants with rheumatoid arthritis who previously received long-term therapy with intravenous abatacept

Official Title
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A Phase 3B Multi-center Open-Label Study to Evaluate the Safety of Abatacept in Subjects Who Switch From Intravenous to Subcutaneous Abatacept Therapy

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recruitment from 2 Bristol-Myers Squibb (BMS) studies (BMS IM101-029 [NCT00048581] and BMS IM101-102 [NCT00048568]). Completion of final quarterly dosing visit in NCT00048581 or NCT00048568 as follows: US and Canadian participants: Day 1821 visit; Taiwanese participants: Day 1905 visit; Mexican participants: Day 1989 visit. Agreement to participate in BMS IM101-185 (NCT00663702) on final quarterly dosing visit in NCT00048581 or NCT00048568 study as follows: US and Canadian participants: Day 1821 visit; Taiwanese participants: Day 1905 visit; Mexican participants: Day 1989 visit. At the time of completion of the NCT00048581 or NCT00048568 protocol, participant did not meet any criteria requiring their discontinuation. Drug stabilization requirements: Participants who received concomitant medications (disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal anti-inflammatory drugs) at the time of their last quarterly dosing visit for NCT00048581 or NCT00048568 were required to maintain stable dose levels from the time they signed consent until the end of the first 3 months (Day 85) of the current study. Willingness to self-inject study medication (abatacept) or allow a caregiver to inject study medication. Willingness to adhere to study visit schedule and comply with other protocol requirements. Male or female (not nursing or pregnant)genders, at least 18 years of age. Women of childbearing potential (WOCBP) must have been practicing adequate contraceptive measures during the study and for up to 10 weeks after the last infusion of study medication in such a manner that the risk of pregnancy was minimized. WOCBP must have had a negative serum or urine pregnancy test result (minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 48 hours prior to the start of study medication. Exclusion Criteria: The following treatment or therapies should not be started on or after the final quarterly dosing visit from the NCT00048581 or NCT00048568 study: Any biologic; immunoabsorption columns (such as Prosorba columns); mycophenolate mofetil; cyclosporin A or other calcineurin inhibitors; D-penicillamine; any live vaccines within 3 months of Day 1 or scheduled to receive a live vaccine during the course of the study Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, or a concomitant medical condition that, in the opinion of the Investigator, might have placed the participation at unacceptable risk for study participation Any clinical laboratory test result that was considered to be abnormal or not within acceptable limits on the final quarterly dosing visit of NCT00048581 or NCT00048568. Screening laboratory test results for NCT00663702 were based on the Day 1821 visit of NCT00048581 or NCT00048568 for participants enrolled at sites in the US or Canada and on the Day 1989 visit of NCT00048568 for participants enrolled at sites in Mexico. Imprisonment or involuntarily incarceration for treatment of either a psychiatric or physical (eg, infectious disease) illness Impairment, incapacitation, inability to complete study-related assessments, or illiteracy.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Abatacept<br>* Subcutaneous injection, 125 mg/mL, once weekly, 48 months<br>* Other names: BMS-188667;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Treatment-related Adverse Events (AEs), AEs Leading to Discontinuation, and AEs of Interest (AEIs) at Day 85 | An AE is a new or worsening illness, sign, or symptom or a clinically significant abnormal laboratory test result occurring during the study, regardless of causality, and noted by the investigators. Systemic injection reaction occurring ≤ 24 hours after dosing. | Day 1 (Baseline) through Day 85 | 
| Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | An AE is a new or worsening illness, sign, or symptom or a clinically significant abnormal laboratory test result occurring during the study, regardless of causality, and noted by the investigators. | Day 1 (Baseline) through 56 days past last day of subcutaneous injection in the cumulative study period | 
| Number of Participants With Hematology Laboratory Values Meeting the Criteria for Marked Abnormality | LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment. Marked abnormality criteria: Hemoglobin (g/dL) >3 decrease from preRx. Hematocrit (%)<0.75*preRx. Erythrocytes (*10^6 c/uL) <0.75*preRx. Platelet count (*10^9 c/L) <0.67*LLN or 1.5*ULN or, if preRx<LLN, use <0.5*preRx and <100,000 mm^3. Leukocytes (*10^3 c/uL) <0.75*LLN or >1.25*ULN or, if preRx<LLN, use <0.8*preRx or >ULN or, if preRx>ULN, use >1.2*preRx or <LLN. Eosinophils >0.750*10^3 c/uL. Lymphocytes <0.750*10^3 c/uL or >7.50*10^3 c/uL. | Day 1 (Baseline) through 56 days past last day of subcutaneous injection in the cumulative study period | 
| Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality | LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment. Marked abnormality criteria: Alkaline phosphatase (U/L) >2*ULN or if preRx>ULN, use 3*preRx. Alanine aminotransferase (U/L)>3*ULN or if preRx>ULN, use >4*preRx. G-glutamyl transferase (U/L)>2*ULN or if preRx>ULN, use >3*preRx. Blood urea nitrogen (mg/dL)>2*preRx. Creatinine (mg/dL)>1.5*preRx. | Day 1 (Baseline) through 56 days past last day of subcutaneous injection in the cumulative study period | 
| Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality | LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment. Sodium: <0.95*LLN or >1.05*ULN or if preRx<LLN, <0.95*preRx or >ULN, or if preRx>ULN,>1.05*preRx or <LLN. Potassium,serum: <0.9*LLN or >1.1*ULN or if preRx<LLN, use <0.9*preRx or >ULN or if preRx>ULN, 1.1*preRx or <LLN. Phosphorus: 0.75*LLN or 1.25*ULN or, if preRx<LLN, <0.67*preRx or >ULN or, if preRx>ULN, <LLN. | Day 1 (Baseline) through 56 days past last day of subcutaneous injection in the cumulative study period | 
| Number of Participants With Chemistry Laboratory Values Meeting the Criteria for Marked Abnormality | LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Criteria for marked abnormality: . | Day 1 (Baseline) to up to 56 days past the last day of subcutaneous injection in the cumulative study period | 
| Participants With Urinalysis Values Meeting the Criteria for Marked Abnormality | preRX=pretreatment. For all values analyzed (protein, urine; glucose, urine; blood, urine: leukocyte esterase, urine; white blood cells, urine; red blood cells, urine): If missing preRx, use >=2 or, if value >= 4, or if preRx=0 or 0.5, use >=2 or, if preRx= 1, use >=3 or, if preRx=2 or 3, use >=4. | Day 1 (Baseline) through 56 days past last day of subcutaneous injection in the cumulative study period | 
| Number of Participants With Adverse Events of Special Interest | AEs of special interest are AEs that may be associated with the use of immunomodulatory drugs, such as infections, malignancies, autoimmune disorders, and injection reactions (defined as local injection site reactions and systemic injection reactions occurring within 24 hours of subcutaneous injection). | Day 1 (Baseline) to up to 56 days past the last day of subcutaneous injection in the cumulative study period | 
| Mean Sitting Systolic and Diastolic Blood Pressure (BP) | BP was measured after the patient had been seated quietly for at least 5 minutes and recorded during the screening visit, during every office visit prior to administration of subcutaneous injections, and at study discharge or 7 days after the last dose for patients who terminated early. | Before injection on Days 1, 29, 57, 85, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541, 1625, 1709, and 1821 | 
| Mean Heart Rate | Heart rate was measured after the patient had been seated quietly for at least 5 minutes and recorded during the screening visit, during every office visit prior to administration of subcutaneous injections, and at study discharge or 7 days after the last dose for patients who terminated early. | Before injection on Days 1, 29, 57, 85, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541, 1625, 1709, and 1821 | 
| Mean Temperature | Temperature was measured after the patient had been seated quietly for at least 5 minutes and recorded during the screening visit, during every office visit prior to administration of subcutaneous injections, and at study discharge or 7 days after the last dose for patients who terminated early. | Before injection on Days 1, 29, 57, 85, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541, 1625, 1709, and 1821 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Trough Serum Concentration (Cmin) of Abatacept | Cmin of abatacept was determined from serum samples. | Days 29, 85, 57, and 85 | 
| Percentage of Participants With A Positive Anti-abatacept Response (Based on Enzyme-linked Immunosorbent Assay [ELISA]) at Day 85 | Using the ELISA, any positive (titer of 400 or greater) postbaseline sample was classified as positive immunogenicity. The percentage of participants with at least 1 positive antibody response (anti-abatacept and/or anti-CTLA4-T) during the 85 days was tabulated by antibody specificity and overall. | Day 1 (Baseline) through Day 85 | 
| Percentage of Participants With A Positive Anti-abatacept Response (Based on Electrochemiluminescence [ECL] Immunoassay) at Day 85 | Number of participants was tabulated using ECL assay with at least 1 positive abatacept-induced immunogenic response (CTLA4 and possibly Ig, Ig and/or Junction Region) in the first 85 days. Positive response (titers >10) included: A missing baseline immunogenicity measurement and a positive immunogenicity response postbaseline A negative baseline immunogenicity response and a positive immunogenicity response postbaseline A positive baseline immunogenicity response and a positive immunogenicity response postbaseline that has a titer value strictly greater than the baseline titer value | Day 1 (Baseline) through Day 85 | 
| Mean Disease Activity Score 28 Based on C-reactive Protein (DAS 28-CRP) Scores Over Time | The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), C-reactive protein level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.) | Day 1 (Baseline) through Day 1093 | 
| Percentage of Participants With Low Disease Activity Score (LDAS) and Disease Activity Score 28 Based on C-reactive Protein (DAS 28-CRP) Remission Over Time: | LDAS is defined as DAS 28-CRP ≤3.2. DAS 28-CRP remission is defined as DAS 28-CRP <2.6. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), C-reactive protein level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.) | Day 1 (Baseline) through Day 1093 | 
| Mean Health Assessment Questionnaire-Disability Index (HAQ-DI) Scores Over Time | The HAQ-DI assesses patients' functional ability by rating their abilities over the previous week. At least 2 questions are asked from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories is divided by the number of categories answered, yielding a score from 0-3. | Day 1 (Baseline) to Day 1093 |