A Phase III Study of Abatacept in Japanese Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the safety of chronic use of abatacept in Japanese Subjects with Rheumatoid Arthritis (RA) having completed clinical studies IM101-071, IM101-034, and also Disease Modifying Anti-Rheumatic Drugs (DMARDs) failures with MTX intolerance.

Official Title
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A Phase III, Multi-center, Open-label, Uncontrolled, Long-term Study to Evaluate the Safety of Abatacept (BMS-188667) in Japanese Subjects With Rheumatoid Arthritis Having Completed Clinical Studies IM101-071, IM101-034, and Also Special DMARD Failures

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria The participants who completed the 169 days, full study period of Phase II (IM101-071) and were not administered other biologics between completion of IM101-071 and registration of this long-term study. The participants of the Phase I study (IM101-034), who received abatacept, except participants who were withdrawn from the study due to safety problems related to abatacept. New subjects with MTX intolerance: rheumatoid arthritis (RA) patients to whom MTX cannot be administered for safety reasons and who present an inadequate response to disease-modifying antirheumatic drugs (DMARDs;excluding MTX) or biologics (new subjects with MTX intolerance: RA patients who present an inadequate response to DMARDs). Exclusion Criteria Women of childbearing potential (WOCBP) who were unwilling or unable to use an acceptable method of contraception. Participants who have received non approved or investigational biologics (other than abatacept from previous or ongoing studies in Japan) at registration. Participants who have received treatment with any investigational drug within 56 days before registration or five half-lives (whichever is the longest). Participants currently receiving treatment with leflunomide, mycophenolate mofetil, calcineurine inhibitors such as cyclosporine and tacrolimus, D-Penicillamine, Cyclophosphamide, or immunoadsorption columns. The participants who completed Phase II (IM101-071) are not applicable in the following instances at time of registration: with active vasculitis, symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, breast cancer, or a history of cancer within the last 5 years, evidence of active or latent bacterial , viral infections, any serious or chronic, at risk of tuberculosis (TB), with any opportunistic infections, laboratory values of hemoglobin < 8.5 g/dL, white blood cells (WBC) < 3,000/mm^3, Platelets < 100,000/mm^3, Serum creatinine > 2 times upper limit of normal (ULN), Serum alanine transaminase or aspartate aminotransferase > 2 times ULN.

Ages Eligible for Study
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Minimum Age: 20 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: Arm 1: Participants from Phase I study (IM101-034)<br> | Drug: Abatacept<br>* Vials (250 mg/vial), Intravenous, Weight-tiered dose of abatacept (equivalent to 10 mg/kg) based on their body weight at the enrollment visit; 500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1,000 mg for participants > 100 kg, administered over a period of approximately 30 minutes at week 0, 2, 4 and every 4 weeks thereafter, until approved in Japan and was continued as a post-marketing study until the completion of the shift to a commercially available product.<br>* Other names: BMS-188667;|
| Experimental: Arm 2: Participants from Phase II study (IM101-071)<br> | Drug: Abatacept<br>* Vials (250 mg/vial), Intravenous, Weight-tiered dose of abatacept (equivalent to 10 mg/kg) based on their body weight at the enrollment visit; 500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1,000 mg for participants > 100 kg, administered over a period of approximately 30 minutes at week 0, 2, 4 and every 4 weeks thereafter, until approved in Japan and was continued as a post-marketing study until the completion of the shift to a commercially available product.<br>* Other names: BMS-188667;|
| Experimental: Arm 3: New Participants with Methotrexate (MTX) Intolerance<br> | Drug: Abatacept<br>* Vials (250 mg/vial), Intravenous, Weight-tiered dose of abatacept (equivalent to 10 mg/kg) based on their body weight at the enrollment visit; 500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1,000 mg for participants > 100 kg, administered over a period of approximately 30 minutes at week 0, 2, 4 and every 4 weeks thereafter, until approved in Japan and was continued as a post-marketing study until the completion of the shift to a commercially available product.<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 Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to AEs | AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is 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 cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event. Both subjective and objective AEs and SAEs are included. | From initiation of the study drug (31 Mar 2008) to data cutoff (27 Dec 2010). The overall mean duration of exposure to the study drug was approximately 3 years (34.3 ± 10.7 months). | 
| Number of Participants With Abnormal Laboratory Changes (ALC) | The laboratory tests were analyses included enzyme, gastrointestinal, hematology, hepatobiliary, lipid, metabolic, nutritional, blood gas, microbiology, serology, protein, chemistry, renal, urinary tract, urinalyses, water, electrolyte and mineral investigations. | From initiation of the study drug (31 Mar 2008) to data cutoff (27 Dec 2010). The overall mean duration of exposure to the study drug was approximately 3 years (34.3 ± 10.7 months). | 
| Number of Participants With Vital Signs, Physical Examinations, and Electrocardiogram Findings That Were Considered to be AEs by the Investigator |  | At week 0, 2, 4; then once every 4 weeks up to 48 months; then once in every 3 months or 12 weeks to end of study (27 Dec 2010). The overall mean duration of exposure to the study drug was approximately 3 years (34.3 ± 10.7 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With American College of Rheumatology (ACR 20) Response Over Time | ACR 20 response requires a participant to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant global assessment of pain, C-reactive protein, and degree of disability in Health Assessment Questionnaire score. | At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. | 
| Percentage of Participants With ACR 50 Response Over Time | ACR 50 response requires a participant to have a 50% reduction in the number of swollen and tender joints, and a reduction of 50% in three of the following five parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant global assessment of pain, C-reactive protein, and degree of disability in Health Assessment Questionnaire score. | At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. | 
| Percentage of Participants With ACR 70 Response Over Time | ACR 70 response requires a participant to have a 70% reduction in the number of swollen and tender joints, and a reduction of 70% in three of the following five parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant global assessment of pain, C-reactive protein, and degree of disability in Health Assessment Questionnaire score. | At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. | 
| Baseline (BL) and Postbaseline (PBL) Disease Activity Scores (DAS 28) | The DAS 28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and participant assessment of disease activity measure on a visual analogue scale of 100 mm. The DAS28 has numeric thresholds that define high disease activity (change of > 5.1), low disease activity (change of ≤ 3.2) and remission (< 2.6). Please see outcome 8 for change from BL data. | At BL (week 0), week 24, 48, 96, 144, and 192. | 
| Change From Baseline in DAS 28 Scores at Week 24, 48, 96, 144, and 192 | The DAS 28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and participant assessment of disease activity measure on a visual analogue scale of 100 mm. The DAS28 has numeric thresholds that define high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Please refer to outcome 7 for BL and PBL values. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Number of Participants With DAS 28 Score Change ≥ 1.2 From Baseline at Weeks 24, 48, 96, 144, and 192 | The DAS 28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and participant assessment of disease activity measure on a visual analogue scale. Participants with DAS 28 score change ≥ 1.2 from BL were considered to have improvement. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Number of Participants With Low Disease Activity Score (DAS 28 Score ≤ 3.2) at Weeks 24, 48, 96, 144, 192 | The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and participant assessment of disease activity measure on a visual analogue scale. Participants with DAS 28 score ≤ 3.2 were considered to have low disease activity. | At weeks 24, 48, 96, 144, and 192. | 
| Number of Participants in Remission (DAS 28 Score < 2.6) at Weeks 24, 48, 96, 144, 192 | The DAS 28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and participant assessment of disease activity measure on a visual analogue scale. Participants with DAS 28 score < 2.6 were considered to be in remission. | At weeks 24, 48, 96, 144, and 192. | 
| Percentage of Participants Who Achieved a Reduction of At Least 0.3 Units From Baseline in Health Assessment Questionnaire (HAQ) at Weeks 24, 48, 96, 144, 192 | The disability section of the full HAQ 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 response=an improvement of at least 0.3 units from BL in HAQ. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Baseline and Postbaseline Physical Component Summary (PCS) of Health-Related Quality of Life (SF-36) Scores | The SF-36 covers 8 health dimensions including 4 physical subscales (physical function, role functioning [physical], bodily pain, and general health) and 4 mental subscales (vitality, social function, role emotional, and mental health). All subscales were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Improvements of > 3 points were considered clinically meaningful.Please see outcome 14 for change from BL data. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Change From Baseline in Physical Component Summary (PCS) of Health-Related Quality of Life (SF-36) Score at Weeks 24, 48, 96, 144, and 192 | The SF-36 covers 8 health dimensions including 4 physical (physical function, role functioning [physical], bodily pain, and general health) and 4 mental subscales (vitality, social function, role emotional, and mental health). All subscales were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from a minimum of 0 to a maximum of 100, higher score indicating better quality of life. Improvements of >3 points were considered clinically meaningful. Please see outcome 13 for BL and PBL values. | At baseline (week 0), weeks 24, 48, 96, 144, and 192. | 
| Baseline and Postbaseline Mental Component Summary (MCS) of Health-Related Quality of Life (SF-36) Scores | The SF-36 covers 8 health dimensions including 4 physical subscales (physical function, role functioning [physical], bodily pain, and general health) and 4 mental subscales (vitality, social function, role emotional, and mental health). All subscales were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Improvements of > 3 points were considered clinically meaningful. Please see outcome 14 for change from BL data. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Change From Baseline in Mental Component Summary (MCS) of Health-Related Quality of Life (SF-36) Score at Weeks 24, 48, 96, 144, and 192 | The SF-36 covers 8 health dimensions including 4 physical (physical function, role functioning [physical], bodily pain, and general health) and 4 mental subscales (vitality, social function, role emotional, and mental health). All subscales were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from a minimum of 0 to a maximum of 100, higher score indicating better quality of life. Improvements of > 3 points were considered clinically meaningful.Please see outcome 15 for BL and PBL values. | At BL (Week 0), weeks 24, 48, 96, 144, and 192. | 
| Baseline and Postbaseline C-reactive Protein (CRP) Levels | CRP is an acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA) and is a core component of the ACR scoring system. CRP was evaluated from serum samples. Increasing levels indicate increasing level of disease. Please see outcome 18 for change from BL data. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Percentage Decrease in C-reactive Protein Levels From Baseline at Weeks 24, 48, 96, 144, and 192 | CRP is an acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA) and is a core component of the ACR scoring system. CRP was evaluated from serum samples. Increasing levels indicate increasing level of disease, negative values indicate improvement. Percentage improvement from BL = (BL - PBL value) / BL value * 100. Please refer to outcome 17 for BL and PBL values. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Baseline and Postbaseline Rheumatoid Factor Levels | Rheumatoid factor (RF or RhF) 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. RF levels are considered positive if value is >20 and considered negative if value is <20. Please see outcome 20 for change from BL data. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Change From Baseline in Rheumatoid Factor Levels at Weeks 24, 48, 96, 144, and 192 | 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. RF levels are considered positive if value is >20 and considered negative if value is <20. Please refer to outcome 19 for BL and PBL values. | At BL (week 0), weeks 24, 48, 96, 144, and 192. | 
| Number of Participants Who Were Positive for Anti-abatacept and Anti-CTLA4-T Antibodies | Validated enzyme-linked immunoassay (ELISA) method was used to measure anti-abatacept and anti-CTLA4-T antibody levels. 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. | At BL (week 0), weeks 24, 48, 72, 96, 120, 144, 168, and 192. | 
| Abatacept PK Parameter: Total Body Clearance | Total body clearance is the rate and extent at which the drug is eliminated from the body. The clearance of a drug is used to understand the processes involved in drug elimination, distribution and metabolism. | Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. | 
| Abatacept PK Parameter: Area Under the Serum Concentration-time Curve at Steady State | Area under the plasma concentration-time curve (AUCss) at steady state for each dosing interval was determined using the linear trapezoidal rule. | Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. | 
| Abatacept PK Parameter: Maximum Serum Concentration at Steady State | Maximum plasma concentration is the maximum observed serum drug concentration at steady state (Css max). | Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. | 
| Abatacept PK Parameter: Minimum Plasma Concentration at Steady State | Minimum Plasma Concentration (Cmin) is the minimum observed serum drug concentration at steady state. | Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. |