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Completed

NCT Number: NCT01001832

Efficacy, Pharmacokinetics, Safety, and Immunogenicity Study of Abatacept Administered Subcutaneously to Treat Rheumatoid Arthritis in Japanese Patients

The purpose of this study is to assess the efficacy, pharmacokinetics, safety, and immunogenicity of abatacept after subcutaneous and intravenous administration in Japanese participants with active rheumatoid arthritis and inadequate response to methotrexate.

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Key information

Conditions

Rheumatoid Arthritis Arthritis Arthritis, Rheumatoid Autoimmune Diseases Connective Tissue Diseases Immune System Diseases Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Skin and Connective Tissue Diseases

Age range

20 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Local Institution, Narita-Shi, Chiba, Japan

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria:

  • Meeting criteria of the American Rheumatism Association for the diagnosis of rheumatoid arthritis (RA) and the American College of Rheumatology functional Classes I, II, or III.
  • Inadequate response (as deemed by investigator) to methotrexate taken for at least 3 months (12 weeks) at a stable dose (6 to 8 mg/week) for 28 days prior to randomization (Day 1).
  • Stabilization requirements for concomitant therapy: Oral corticosteroid treatment reduced to the equivalent of ≤10 mg prednisolone daily for 28 days and stabilized for at least 25 of 28 days prior to treatment (Day 1). No intra-articular, intravenous, or intramuscular injections of corticosteroids were permitted within 28 days prior to randomization (Day 1.)
  • Washout requirements: Participants receiving combination RA therapy had to discontinue the following therapies at least 28 days prior to treatment (Day 1):

disease-modifying antirheumatic drugs (DMARDs), such as gold (auranofin and aurothiomalate sodium), actarit, bucillamine, azathioprine, salazosulfapyridine, lobenzarit disodium, D-penicillamine, cyclophosphamide, mycophenolate mofetil, mizoribine; cyclosporin, tacrolimus, and other calcineurin inhibitors; and immunoadsorption columns.

  • Disease Activity Requirements: At randomization (Day 1), participants had to meet the following disease activity criteria: Swollen joint count: 10 or more swollen joints (66 joint count); tender joint count: 12 or more tender joints (68 joint count); C reactive protein (CRP): ≥0.8 mg/dL (result from screening visit).
  • For participants receiving methotrexate plus other DMARDs(washout of a combination therapy required): At screening visit, participants had to meet the following disease activity criteria: Swollen joint count: 6 or more swollen joints (66 joint count); tender joint count: 8 or more tender joints (68 joint count); CRP: no restriction on CRP (not applicable).
  • After washout, at randomization (Day 1), participants must meet the following disease activity criteria: Swollen joint count-10 or more swollen joints (66 joint count) and tender joint count-12 or more tender joints (68 joint count) and CRP: ≥0.8 mg/dL (result from screening visit). For those whose screening period were longer than 4 weeks, CRP test needed to be performed on Day
  • 28 to Day -3 (prior to treatment Day 1) to verify eligibility.

Key Exclusion Criteria:

  • Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease. Concomitant medical conditions that, in the opinion of the investigator, might place the participant at unacceptable risk for participation in this study.
  • Female participants who had undergone breast cancer screening that was suspicious for malignancy, and in whom the possibility of malignancy could not be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations.
  • History of cancer within the last 5 years (other than nonmelanoma skin cell cancers cured by local resection)
  • Existing nonmelanoma skin cell cancers had been removed prior to the first administration. Participants with carcinoma in situ, treated with definitive surgical intervention prior to study entry were allowed to participate.
  • Clinically significant drug or alcohol abuse
  • Any serious acute bacterial infection (such as pneumonia or pyelonephritis unless treated and completely resolved with antibiotics)
  • Serious, chronic, or recurrent bacterial infections (such as recurrent pneumonia, chronic bronchiectasis)
  • Those at risk for tuberculosis (TB). Specifically, those with current clinical, radiographic, or laboratory evidence suggestive of active TB; history of active TB within the last 3 years, even if treated; history of active TB more than 3 years ago unless there was documentation that the prior anti-TB treatment was appropriate in type and duration; latent TB that was not successfully treated. Participants with a positive result on TB screening test indicative of latent TB were not eligible for the study unless active TB infection had been ruled out and treatment for latent TB with isoniazid had been initiated for at least 4 weeks prior to administration of the study drug and the participant had a negative finding for TB on a chest X-ray film at enrollment.
  • Herpes zoster resolving less than 2 months prior to enrollment
  • Current evidence (as assessed by the investigator) suggestive of active or latent bacterial or viral infections, including human immunodeficiency virus infection.
  • Physical examination and laboratory test findings: Hepatitis B surface antigen-positive status; hepatitis C antibody-positive status. Any of the following laboratory values: Hemoglobin concentration: <.5 g/dL; white blood cell count: <3,000/μL (3*10^9/L); platelet count: <100,000/mm^3(100*10^9/L); serum creatinine: >2 times upper limit of normal (ULN); serum alanine aminotransferase: >2 ULN; serum aspartate aminotransferase: >2 ULN.
  • Prohibited treatments and/or therapies: Prior exposure to abatacept (CTLA4-Ig); prior RA treatment with any biologics, such as anti-tumor necrosis factor therapy; prior exposure to any investigational biologic not currently approved in Japan; exposure to any study medication in any other previous study within 4 weeks or 5 half-lives, whichever was longer; receipt of any live vaccines within 3 months of administration of study medication or scheduled to receive live vaccines.

Treatment and study plan

Intravenous (IV) abatacept

Drug

IV vial, 125-mg infusions on Days 1, 15, and 29, and every 28 days thereafter until Day 141.

Other names: BMS-188667

Subcutaneous (SC) abatacept

Drug

Solution in prefilled syringes, SC, 125 mg, once weekly, for 169 days and then for 52 weeks

Other names: BMS-188667

Primary outcomes

  1. Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Day 169 in Short Term Period

    Time frame: Day 169

    The ACR score of 20 indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines (ACR20). The ACR score represents a percentage. To qualify for an ACR20 score, the patient must have >=20% fewer tender joints and >=20% fewer swollen joints and show 20% improvement in at least 3 of: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation). Percentage is calculated n/N with n=number of participants with ACR score of 20 and N= all randomized participants who received at least one dose of study drug.

  2. Percentage of Participants With Sustained American College of Rheumatology (ACR) Response at Day 533 in Long Term Period - All Randomized and Treated Participants During the Long Term Period

    Time frame: Day 533

    The ACR score indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines. The ACR score= a percentage. To qualify for a score of 20, 50 or 70 (ACR20, ACR50 or ACR70), the patient must have >=20%, >=50% or >=70%, respectively, fewer tender joints and >=20%, >=50% or >=70%, respectively, fewer swollen joints and show 20%, 50% or 70%, respectively, improvement in at least 3 of the following: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation). Treatment groups represent treatment received in the short term period. Percentage calculated as n/m with n=number of paticipants with sustained ACR response at Day 533; m= long term participants who received at least one dose of drug and were ACR responders in the short term period.

  3. Mean Change From Baseline in HAQ-DI Score at Day 533 in Long Term Period

    Time frame: Baseline to Day 533

    Adjusted mean. The Health Assessment Questionnaire Disability Index (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 score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. Treatment groups represent treatment received in the short term period. Baseline is Day 1 of the study or last non-missing pre-treatment value.

  4. Percentage of Participants With Health Assessment Questionnaire (HAQ) Response at Day 533 in Long Term Period

    Time frame: Day 533

    The Health Assessment Questionnaire (HAQ) disability index 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 higher the number the worse the outcome. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. HAQ response=reduction of at least 0.30 units in HAQ score from baseline. The percentage of participants with a reduction of at least 0.30 units in their HAQ score from baseline is presented. Baseline is Day 1 of the study or last non-missing pre-treatment value. Treatment groups represent treatment received in the short term period.

  5. Mean Change in DAS28-CRP From Baseline at Day 533 in Long Term Period

    Time frame: Baseline to Day 533

    The Disease Activity Score 28 using C-Reactive Protein (DAS28-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), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). An overall DAS >5.1 implies active disease; <3.2, well controlled disease; and <2.6, remission.). Treatment groups represent treatment received in the short term period. Baseline is Day 1 of the study or last non-missing pre-treatment value.

Secondary outcomes

  1. Percentage of Participants With American College of Rheumatology 50 (ACR50) and American College of Rheumatology 70 (ACR70) Responses at Day 169 in Short Term Period

    Time frame: Day 169

    The American College of Rheumatology (ACR) scores of 50 and 70 indicates the degree of improvement in a patient's rheumatoid arthritis (RA), based on ACR guidelines. The ACR score represents a percentage. To qualify for an ACR50 or ACR70 scores, the patient must have >=50% or >=70%, respectively, fewer tender joints and >=50% or >=70%, respectively, fewer swollen joints and show 50% or 70%, respectively, improvement in at least 3 of the following: patient overall assessment of his/her RA, physician global assessment of the patient's RA, patient self-assessment of pain, patient self-assessment of physical functioning, and results of an erythrocyte sedimentation rate or C-reactive protein test (to assess inflammation).

  2. Mean Change From Baseline in HAQ-DI Score at Day 169 in Short Term Period

    Time frame: Baseline to Day 169

    Adjusted mean. The Health Assessment Questionnaire Disability Index (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 score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3.

  3. Percentage of Participants With HAQ Response at Day 169 in the Short Term Period

    Time frame: Day 169

    The Health Assessment Questionnaire Disability Index (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 score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. The HAQ-DI response is defined as a reduction of at least 0.30 units in HAQ score from baseline.

  4. Mean Change From Baseline at Six Months in DAS28-CRP - All Treated Participants

    Time frame: Baseline to 6 Months

    The Disease Activity Score 28 using C-Reactive Protein (DAS28-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), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). An overall DAS >5.1 implies active disease; <3.2, well controlled disease; and <2.6, remission.). Baseline is Day 1 or last non-missing pre-treatment value.

  5. Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and EULAR-defined Remission (REM) at Day 169 in Short Term Period

    Time frame: Day 169

    EULAR defines LDAS as DAS28-CRP less than, equal to (≤) 3.2 and defines REM as DAS28-CRP less than (<) 2.6.

  6. Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and EULAR-defined Remission (REM) at Day 533 in Long Term Period

    Time frame: Day 533

    EULAR defines LDAS as DAS28-CRP≤3.2 and defines REM as DAS28-CRP<2.6.

  7. Short-term Period: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, and Discontinuations Due to AEs

    Time frame: Baseline to Day 169

    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. Treatment-related=related or missing relationship to study medication.

  8. Long-term Period: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, and Discontinuations Due to AEs

    Time frame: Baseline to Day 533 and up to 56 days following last dose in Long-Term period

    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. Treatment-related=related or missing relationship to study medication.

  9. Short-term Period: Number of Participants With Hematology Laboratory Values Meeting the Criteria for Marked Abnormality

    Time frame: Baseline to Day 169

    lower limit of normal(LLN); upper limit of normal(ULN); pretreatment(preRX). Hemoglobin (g/dL): >3 g/dL decrease from preRX; hematocrit (%): <0.75*preRX; erythrocytes (*10^6 c/uL): <0.75*preRX; platelet count (*10^9 c/uL): <0.67*LLN or >1.5*ULN, of 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; neutrophils+bands (*10^3 c/uL): if value <1.0*10^3 c/uL; eosinophils (*10^3 c/uL): if value >0.750*10^3 c/uL; basophils (*10^3 c/uL): if value >400/mm^3; monocytes (*10^3 c/uL): if value >2000/mm^3; lymphocytes (*10^3 c/uL): if value <0.750*10^3 c/uL or if value >7.50*10^3 c/uL.

  10. Long-term Period: Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria

    Time frame: Baseline to Day 533

    LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Hemoglobin (g/dL): >3 g/dL decrease from preRX; hematocrit (%): <0.75*preRX; erythrocytes (*10^6 c/uL): <0.75*preRX; platelet count (*10^9 c/uL): <0.67*LLN or >1.5*ULN, of 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; neutrophils+bands (*10^3 c/uL): if value <1.0*10^3 c/uL; eosinophils (*10^3 c/uL): if value >0.750*10^3 c/uL; basophils (*10^3 c/uL): if value >400/mm^3; monocytes (*10^3 c/uL): if value >2000/mm^3; lymphocytes (*10^3 c/uL): if value <0.750*10^3 c/uL or if value >7.50*10^3 c/uL.

  11. Short-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality

    Time frame: Baseline to Day 169

    ULN=upper limit of normal; LLN=lower limit of normal; preRX=pretreatment. alkaline phosphatase (ALP) (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; aspartate aminotransferase (AST) (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; alanine aminotransferase(ALT) (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; Gamma glutamyltransferase(GGT) (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; bilirubin (mg/dL): >2*ULN, or if preRX>ULN, use >4*preRX; blood urea nitrogen (mg/dL): >2*preRX; creatinine (mg/dL): >1.5*preRX.

  12. Short-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality

    Time frame: Baseline to Day 169

    LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Sodium (mEq/L): <0.95*LLN or >1.05*ULN, or if preRX<LLN, use <0.95*preRX or >ULN, or if preRX>ULN, use 1.05*preRX or <LLN; potassium (mEq/L): <0.9*LLN or >1.1*ULN, or if preRX<LLN, use <0.9*preRX or >ULN, or if preRX>ULN, use 1.1*preRX or <LLN; chloride (mEq/L): <0.75*LLN or >1.125*ULN, or if preRX<LLN, use <0.75*preRX or >ULN, or if preRX>ULN, use 1.25*preRX or <LLN; calcium (mg/dL): <0.75*LLN or >1.25*ULN, or if preRX<LLN, use <0.75*preRX or >ULN, or if preRX>ULN, use 1.25*preRX or <LLN; phosphorus (mg/dL): <0.75*LLN or >1.25*ULN, or if preRX<LLN, use <0.67*preRX or >ULN, or if preRX>ULN, use 1.33*preRX or <LLN.

  13. Long-term Period: Number of Participants With Liver and Kidney Function Laboratory Values Meeting the Criteria for Marked Abnormality

    Time frame: Baseline to Day 533

    ULN=upper limit of normal; LLN=lower limit of normal; preRX=pretreatment. ALP (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; AST (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; ALT (U/L): >3*ULN, or if preRX>ULN, use >4*preRX; GGT (U/L): >2*ULN, or if preRX>ULN, use >3*preRX; bilirubin (mg/dL): >2*ULN, or if preRX>ULN, use >4*preRX; blood urea nitrogen (mg/dL): >2*preRX; creatinine (mg/dL): >1.5*preRX.

  14. Long-term Period: Number of Participants With Electrolyte Laboratory Values Meeting the Criteria for Marked Abnormality

    Time frame: Baseline to Day 533

    LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Sodium (mEq/L): <0.95*LLN or >1.05*ULN, or if preRX<LLN, use <0.95*preRX or >ULN, or if preRX>ULN, use 1.05*preRX or <LLN; potassium (mEq/L): <0.9*LLN or >1.1*ULN, or if preRX<LLN, use <0.9*preRX or >ULN, or if preRX>ULN, use 1.1*preRX or <LLN; chloride (mEq/L): <0.75*LLN or >1.125*ULN, or if preRX<LLN, use <0.75*preRX or >ULN, or if preRX>ULN, use 1.25*preRX or <LLN; calcium (mg/dL): <0.75*LLN or >1.25*ULN, or if preRX<LLN, use <0.75*preRX or >ULN, or if preRX>ULN, use 1.25*preRX or <LLN; phosphorus (mg/dL): <0.75*LLN or >1.25*ULN, or if preRX<LLN, use <0.67*preRX or >ULN, or if preRX>ULN, use 1.33*preRX or <LLN.

Sponsors and collaborators

Lead sponsor

Bristol-Myers Squibb

Industry

Registry information

Official study title

A Phase II/III, Multicenter, Randomized, Double-Blind, Double-Dummy Study to Assess Similarity of the Efficacy, Pharmacokinetics, Safety and Immunogenicity of Abatacept Administered Subcutaneously or Intravenously in Japanese Subjects With Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate

Important dates

Study start
2009
Primary completion
2011
Study completion
2012
First posted
Oct 27, 2009
Registry last updated
Feb 6, 2014

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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