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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00484289
First received: June 7, 2007
Last updated: June 18, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Abatacept
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to AEs [ Time Frame: 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). ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Abnormal Laboratory Changes (ALC) [ Time Frame: 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). ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Vital Signs, Physical Examinations, and Electrocardiogram Findings That Were Considered to be AEs by the Investigator [ Time Frame: 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). ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percentage of Participants With American College of Rheumatology (ACR 20) Response Over Time [ Time Frame: At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With ACR 50 Response Over Time [ Time Frame: At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With ACR 70 Response Over Time [ Time Frame: At weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192. ] [ Designated as safety issue: No ]
    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.

  • Baseline (BL) and Postbaseline (PBL) Disease Activity Scores (DAS 28) [ Time Frame: At BL (week 0), week 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in DAS 28 Scores at Week 24, 48, 96, 144, and 192 [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With DAS 28 Score Change ≥ 1.2 From Baseline at Weeks 24, 48, 96, 144, and 192 [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]

    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.


  • Number of Participants With Low Disease Activity Score (DAS 28 Score ≤ 3.2) at Weeks 24, 48, 96, 144, 192 [ Time Frame: At weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants in Remission (DAS 28 Score < 2.6) at Weeks 24, 48, 96, 144, 192 [ Time Frame: At weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]

    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.


  • 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 [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Baseline and Postbaseline Physical Component Summary (PCS) of Health-Related Quality of Life (SF-36) Scores [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: At baseline (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Baseline and Postbaseline Mental Component Summary (MCS) of Health-Related Quality of Life (SF-36) Scores [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: At BL (Week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Baseline and Postbaseline C-reactive Protein (CRP) Levels [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Percentage Decrease in C-reactive Protein Levels From Baseline at Weeks 24, 48, 96, 144, and 192 [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Baseline and Postbaseline Rheumatoid Factor Levels [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Rheumatoid Factor Levels at Weeks 24, 48, 96, 144, and 192 [ Time Frame: At BL (week 0), weeks 24, 48, 96, 144, and 192. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Who Were Positive for Anti-abatacept and Anti-CTLA4-T Antibodies [ Time Frame: At BL (week 0), weeks 24, 48, 72, 96, 120, 144, 168, and 192. ] [ Designated as safety issue: No ]
    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.

  • Abatacept PK Parameter: Total Body Clearance [ Time Frame: Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. ] [ Designated as safety issue: No ]
    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.

  • Abatacept PK Parameter: Area Under the Serum Concentration-time Curve at Steady State [ Time Frame: Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve (AUCss) at steady state for each dosing interval was determined using the linear trapezoidal rule.

  • Abatacept PK Parameter: Maximum Serum Concentration at Steady State [ Time Frame: Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. ] [ Designated as safety issue: No ]
    Maximum plasma concentration is the maximum observed serum drug concentration at steady state (Css max).

  • Abatacept PK Parameter: Minimum Plasma Concentration at Steady State [ Time Frame: Samples were collected predose at week 8, 12, 16, 24; end of infusion at week 12; and at week 13-15 visits. ] [ Designated as safety issue: No ]
    Minimum Plasma Concentration (Cmin) is the minimum observed serum drug concentration at steady state.


Enrollment: 217
Study Start Date: December 2006
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1: Participants from Phase I study (IM101-034) Drug: Abatacept
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.
Other Names:
  • Orencia®
  • BMS-188667
Experimental: Arm 2: Participants from Phase II study (IM101-071) Drug: Abatacept
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.
Other Names:
  • Orencia®
  • BMS-188667
Experimental: Arm 3: New Participants with Methotrexate (MTX) Intolerance Drug: Abatacept
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.
Other Names:
  • Orencia®
  • BMS-188667

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00484289

Locations
Japan
Local Institution
Nagoya, Aichi, Japan, 466-8550
Local Institution
Nagoya-Shi, Aichi, Japan, 460-0001
Local Institution
Goshogawara-Shi, Aomori, Japan, 037-0053
Local Institution
Chiba-Shi, Chiba, Japan
Local Institution
Fukui-Shi, Fukui, Japan, 910-0041
Local Institution
Fukui-Shi, Fukui, Japan, 9103133
Local Institution
Fukui-Shi, Fukui, Japan, 9100067
Local Institution
Fukuoka-Shi, Fukuoka, Japan, 810-0065
Local Institution
Fukuoka-Shi, Fukuoka, Japan, 812-0025
Local Institution
Kitakyushu-Shi, Fukuoka, Japan, 807-8555
Local Institution
Higashi-Hiroshima-Shi, Hiroshima, Japan, 739-0002
Local Institution
Sapporo City, Hokkaido, Japan, 060-8648
Local Institution
Sapporo-City, Hokkaido, Japan, 060-8604
Local Institution
Sapporo-City, Hokkaido, Japan, 060-0001
Local Institution
Kanzaki-Gun, Hyogo, Japan, 679-2414
Local Institution
Kato-Gun, Hyogo, Japan, 673-1462
Local Institution
Hitachi-Shi, Ibaraki, Japan, 316-0035
Local Institution
Tsukuba-Shi, Ibaraki, Japan, 305-0005
Local Institution
Sagamihara-Shi, Kanagawa, Japan, 228-8522
Local Institution
Sendai, Miyagi, Japan
Local Institution
Sendai-Shi, Miyagi, Japan, 982-0032
Local Institution
Sendai-Shi, Miyagi, Japan, 981-0911
Local Institution
Nagano-Shi, Nagano, Japan, 380-8582
Local Institution
Tsukubo-Gun, Okayama, Japan, 701-0304
Local Institution
Kawachinagano-Shi, Osaka, Japan, 86-0008
Local Institution
Ureshino-Shi, Saga, Japan, 843-0301
Local Institution
Iruma-Gun, Saitama, Japan, 350-0495
Local Institution
Kawagoe-Shi, Saitama, Japan, 350-8550
Local Institution
Kitamoto-Shi, Saitama, Japan, 364-0026
Local Institution
Hamamatsu-Shi, Shizuoka, Japan, 430-0906
Local Institution
Kawachigun, Tochigi, Japan, 329-1104
Local Institution
Shimotsuke-Shi, Tochigi, Japan, 3290498
Local Institution
Arakawa-Ku, Tokyo, Japan, 116-0011
Local Institution
Bunkyo-Ku, Tokyo, Japan, 113-0022
Local Institution
Bunkyo-Ku, Tokyo, Japan, 113-8519
Local Institution
Setagaya-Ku, Tokyo, Japan, 155-0032
Local Institution
Shinjuku-Ku, Tokyo, Japan, 162-0054
Local Institution
Takaoka-Shi, Toyama, Japan, 933-8525
Local Institution
Chiba-Shi, Japan, 260-0801
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00484289     History of Changes
Other Study ID Numbers: IM101-129
Study First Received: June 7, 2007
Results First Received: May 25, 2012
Last Updated: June 18, 2013
Health Authority: Japan: Pharmaceuticals and Medical Devices Agency

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 28, 2014