A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Clinical Efficacy of Two Different Doses of BMS-188667 Administered Intravenously to Subjects With Active Rheumatoid Arthritis While Receiving Methotrexate
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 524
- 试验地点
- 1
- 主要终点
- Number of Responders to American College of Rheumatology 20% Improvement Criteria (ACR 20) at Day 180 of the Double-Blind (DB) Period
研究概览
简要总结
This study was conducted to assess the safety and tolerability of Abatacept combined with Methotrexate in participants with active rheumatoid arthritis (RA). The secondary objectives were to assess efficacy, pharmacodynamic marker activity, and immunogenicity of Abatacept combined with Methotrexate.
详细描述
All participants who completed the 12-month double-blind study period were eligible to continue in the open-label study. Participants received placebo, Abatacept 2 mg/kg, or Abatacept 10 mg/kg in the double-blind study. Participants receiving placebo in the double-blind study were switched 1:1 to continued treatment with placebo or Abatacept 2 mg/kg. Participants receiving Abatacept 2 mg/kg or Abatacept 10 mg/kg continued at the double-blind study dosage. After results from the double-blind period became available, all participants were switched to a weight-tiered 10 mg/kg dose of Abatacept.
Open label study design: Single group assignment, Single arm, Open label,
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Double blind study phase:
- •Males or females (not nursing and not pregnant), at least 18 years of age. Women of child bearing potential (WOCBP) are eligible if they are practicing effective contraceptive measures
- •Subjects must meet the criteria of the American Rheumatism Association (1987) for the diagnosis of rheumatoid arthritis and the American College of Rheumatology (1991) functional classes I, II, or III
- •Subjects have been taking Methotrexate (10-30 mg weekly) for at least 6 months, and at a stable dose for 28 days prior to treatment
- •Washout/drug stabilization requirements (except Methotrexate) [Informed consent must be signed before making any changes in RA therapy if those changes are solely for the purpose of this study].
- •Leflunomide or Infliximab have already been discontinued at least 60 days prior to enrollment (prior to signing of informed consent) and a total of 90 days prior to treatment. All other Disease Modifying Anti-Rheumatic Drugs (DMARDs) (except Methotrexate) have been withdrawn at least 28 days prior to treatment
- •Oral corticosteroid treatment has been reduced to the equivalent of 10 mg or less prednisone daily and stabilized for at least 28 days prior to enrollment
- •Eligibility of subjects for the study is based on their disease activity and anti-rheumatic treatment at the initial visit:
- •Methotrexate monotherapy: Subject is receiving only Methotrexate, steroids, Non-steroidal anti-inflammatory drugs (NSAIDs) and will not require washout
- •Combination therapy: Subject is receiving Methotrexate in combination with another DMARD(s) and will require washout
- •At entry, Methotrexate monotherapy must have a disease activity:
- •10 or more swollen joints (66 joint count)
- •12 or more tender joints (68 joint count)
- •C reactive protein (CRP) ≥.1 mg/dL (10 mg/L) at "Screening" visit
- •At entry, combination therapy must have a disease activity (if subject does not satisfy the above):
- •6 or more swollen joints (66 joint count)
- •8 or more tender joints (68 joint count)
- •No restriction on C-reactive protein (CRP)
- •In addition
- •All subjects who were on combination therapy at entry must undergo a 28 day washout period of DMARDs other than Methotrexate. After the washout/drug stabilization and prior to randomization such subjects must have:
- •10 or more swollen joints (66 joint count)
- •12 or more tender joints (68 joint count)
- •C reactive protein (CRP) ≥ 1 mg/dL (10 mg/L)
- •Subject is willing to participate in the study and willing to sign the informed consent
- •Open label study phase:
- •Participants that have completed the initial short term portion (double blind) of the study
排除标准
- •Double blind study phase:
- •Subjects who have at any time received treatment with BMS-188667 (Abatacept)
- •Subjects who within 30 days of the Day 1 visit have received treatment with any investigational drug
- •Subjects with active vasculitis of a major organ system (except for subcutaneous rheumatoid nodules)
- •Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease. Concomitant medical conditions that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study
- •Mammogram requiring further investigation or biopsies leading to the diagnosis of a clinically significant abnormality. Complete evaluation of lesion is required before initiation of dosing
- •Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection)
- •Subjects who have a history of clinically significant drug or alcohol abuse, or admit to consumption of more than 1 alcoholic drink per day
- •Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection, or hepatitis B or C infection
- •Subjects with any serious or chronic infections such as pneumonia, pyelo-nephritis, renal infection, chest infection with bronchiectasis, or sinusitis in the previous 3 months
- •Subjects with active tuberculosis requiring treatment within the previous 3 years
- •Subjects with any opportunistic infections such as herpes zoster or cytomegalovirus (CMV) within the previous 2 months
- •Subjects with severe asthma defined as > 3 emergency room admissions in the last year or > 3 treatments with oral steroids for asthma in the last year
- •A history of either angioedema or anaphylaxis that was associated with a reaction to a drug
- •Subjects with the following laboratory values:
- •Hemoglobin < 8.5 g/dL
- •White blood cells < 3000/mm3
- •Platelets < 100,000/mm3
- •Serum creatinine > 2 times upper limit of normal
- •Serum Alanine aminotransferase (ALAT) or Aspartate aminotransferase (ASAT) > 2 times upper limit of normal
- •Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study
- •Open label study phase:
- •Participants must continue to meet inclusion/exclusion criteria as in the short term (double blind) phase of the protocol except subjects who have receiving other than Abatacept
研究组 & 干预措施
Abatacept (10 mg/Kg) - Open Label
干预措施: Abatacept (BMS-188667) (Drug)
Abatacept (2 mg/kg) - Double blind
干预措施: Abatacept (BMS-188667) (Drug)
Abatacept (10 mg/kg) - Double blind
干预措施: Abatacept (BMS-188667) (Drug)
Placebo - Double blind
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Responders to American College of Rheumatology 20% Improvement Criteria (ACR 20) at Day 180 of the Double-Blind (DB) Period
时间窗: Day 180
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, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.
Participants Receiving Concomitant Disease Modifying Rheumatic Drugs and Biologics in Open-Label (OL) Period
时间窗: Day 360 to Day 3,060
The number of participants receiving concomitant rheumatoid arthritis treatment with disease modifying rheumatic drugs and/or biologics.
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) in OL Period
时间窗: Day 360 to Day 3060
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with treatment.SAE=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 congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related AE/SAE=Certain,Probable,Possible,or Missing relationship to drug.
Baseline Serum Immunoglobulin A (IgA) Over Time in OL Period
时间窗: Baseline (Day 0) and Days 360, 720,1080, 1440, and 1800
Time-matched baseline (Day 0) values and post-baseline values were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 6.
Number of Participants With Electrolyte Values Meeting Marked Abnormality Criteria in OL Period
时间窗: Day 360 to Day 3060
Number of Participants With Glucose, Protein, Metabolites, and Urinalysis Values Meeting Marked Abnormality Criteria in OL Period
时间窗: Day 360 to Day 3060
Number of Participants With AEs of Special Interest in OL Period
时间窗: Day 360 to Day 3060
AEs were defined as any new untoward medical occurrence or worsening of a pre- existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest were those which may be associated with the use of immunomodulatory agents or infusion of therapeutic proteins. Acute infusional AEs were defined as those that occurred within 1 hour after the start of the infusion. Peri-Infusional AEs were defined as those that occurred within 24 hours after the start of the infusion.
Mean Change From Baseline (BL) in IgA Over Time in OL Period
时间窗: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgA. Baseline data for these time-matched cohorts are presented in Outcome Measure 5.
Baseline Immunoglobulin G (IgG) Over Time in OL Period
时间窗: Baseline (Day 0) and Days 360, 720, 1080, 1440 and 1800
Time-matched baseline (Day 0) values and post-baseline vales were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 8.
Mean Change From Baseline (BL) in IgG Over Time in OL Period
时间窗: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgG. Baseline data for these cohorts are presented in Outcome Measure 7.
Baseline Immunoglobulin M (IgM) Over Time in OL Period
时间窗: Baseline (Day 0) and Days 360, 720,1080,1440, and 1800
Time-matched baseline (Day 0) values and post-baseline values were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 10.
Mean Change From Baseline (BL) in IgM in OL Period
时间窗: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgM. Baseline data for these time-matched cohorts are presented in Outcome Measure 9.
Number of Participants With Liver and Kidney Function Values Meeting Marked Abnormality Criteria in OL Period
时间窗: Day 360 to Day 3060
Number of Participants With Hematology Values Meeting Marked Abnormality Criteria in OL Period
时间窗: Day 360 to Day 3060
次要结局
- Number of ACR 20 Responders in DB Period(Days 15, 30, 60, 90, 120, 150,180, 240, 300, and 360)
- Number of ACR 50 Responders in DB Period(Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in Rheumatoid Factor at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in Interleukin-6 at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in Plasma Soluble Interleukin-2 Receptor (sIL-2R) at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in E-Selectin at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in Soluble Inter-Cellular Adhesion Molecule 1 (sICAM-1) at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Pharmacodynamic Measure: Mean Changes From Baseline in Tumor Necrosis Factor (TNF)-Alpha at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Adjusted Mean Percent Changes From Baseline in the Modified Health Assessment Questionnaire (mHAQ) at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Number of Participants With At Least One New Active Joint (Tender Joints and Swollen Joints) at Day 180 and Day 360(Day 180, Day 360)
- Participants Who Experienced Death, Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations During the Double-Blind Period(From the start of study through the end of the double-blind period (at 12 months))
- Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Blood Chemistry Values During Double-Blind Therapy(From the start of study up to 60 days post the end of the 12-month double-blind period)
- Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Hematologic Values During Double-Blind Therapy(From the start of study up to 60 days post the end of the 12-month double-blind period)
- Number of Participants Who Discontinued Due to Lack of Efficacy in the DB and OL Periods(Day 1 to Day 360 (Double-Blind Period), Day 361 to Day 3060 (Open-Label Period))
- Immunogenicity Data: Anti-CTLA4Ig Antibodies With Immunoglobulin (IG) Region(Baseline, Days 30, 90, 180, 270, 360)
- Number of ACR 70 Responders in DB Period(Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360)
- ACR Numeric Values (ACR-N)(Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360)
- ACR-N Area Under The Curve (AUC) on Day 180 and Day 360(Baseline and Day 180; Baseline and Day 360)
- Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 180(Baseline, Day 180)
- Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 360(Baseline, Day 360)
- Mean Changes From Baseline in the Short Form 36 (SF-36) Physical and Mental Health Component Summary Scores (PCS and MCS) at Day 180 and Day 360(Baseline, Day 180, Day 360)
- Immunogenicity Data: Anti-CTLA4Ig Antibodies Without IG Region(Baseline, Days 30, 90, 180, 270, 360)
- Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion (Anti-CTLA4Ig Antibodies With IG Region)(Baseline, Days 30, 90, 180, 270, 360)
- Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion(Anti-CTLA4Ig Antibodies Without IG Region)(Baseline, Days 30, 90, 180, 270, 360)
- Number of ACR 20 Responders in OL Period(Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060)
- Number of ACR 50 Responders in the OL Period(Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060)
- Number of ACR 70 Responders in the OL Period(Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060)
- Number of Participants With a Clinically Meaningful Improvement on the Modified Health Assessment Questionnaire (mHAQ) in OL Period(Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Baseline Level of Serum Rheumatoid Factor Over Time in OL Period(Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline in Serum Rheumatoid Factor Level Over Time in OL Period(Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Soluble Serum Interleukin-2 Receptor Level (sIL2-r) Over Time in OL Period(Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline in sIL2-r Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800)
- Mean Baseline Serum C-Reactive Protein Level Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080,1440,1800, 2160, 2520, 2880, 3060)
- Mean Change From Baseline in Level of C Reactive Protein Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, 3060)
- Mean Baseline Physical Component Summary (PCS) of the Short-Form 36 (SF-36) Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060)
- Mean Change From Baseline (BL) in the Physical Component Summary (PCS) of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060)
- Mean Baseline Mental Component Summary (MCS) of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060)
- Mean Change From Baseline (BL) in the MCS of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060)
- Mean Baseline (BL) Physical Functioning Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Physical Functioning Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Role-Physical Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Role-Physical Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Bodily Pain Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From BL in the Bodily Pain Domain of the SF-36 Over Time in OL Period(BL (Day 0); Day 360; Day 720; Day 1,080; Day 1,440; Day 1,800; Day 2,160; Day 2,520; Day 2,880; Day 3,060)
- Mean BL General Health Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the General Health Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Vitality Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Vitality Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Social Functioning Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Social Functioning Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Role-Emotional Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Role-Emotional Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Baseline Mental Health Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)
- Mean Change From Baseline (BL) in the Mental Health Domain of the SF-36 Over Time in OL Period(Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060)