A Phase IIIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Comparative Study of Abatacept or Infliximab in Combination With Methotrexate in Controlling Disease Activity in Subjects With Rheumatoid Arthritis Having an Inadequate Clinical Response to Methotrexate
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 431
- 试验地点
- 1
- 主要终点
- OL; Mean Change From Baseline to Day 365 in Hematocrit
研究概览
简要总结
The purpose of this clinical research study is to learn if Abatacept or Infliximab in combination with Methotrexate demonstrate a greater reduction in disease activity over placebo.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of Rheumatoid Arthritis
- •At least 3 months prior treatment with Methotrexate (MTX)
- •At least 10 swollen joints and 12 tender joints and C-Reactive Protein of at least 1 mg/dl
- •Washout required for other disease modifying anti-rheumatic drugs (DMARDS)
排除标准
- •participants who have failed more than 3 DMARDs
- •participants previously treated with an approved biologic drug
- •History of cancer in the last 5 years
- •Severe or recurrent bacterial infection
- •Any previous or current medical conditions that are contraindications to the use of TNF blocking agents
- •Women of Child Bearing Potential
研究组 & 干预措施
Abatacept (ABA) + Methotrexate (MTX) (double-blind [DB])
Days 1-365
干预措施: Abatacept (ABA) + Methotrexate (MTX), double-blind (DB) (Drug)
Infliximab + MTX (DB)
Days 1-365
干预措施: Infliximab (INF) + MTX, DB (Drug)
Placebo + MTX (DB)
Days 1-197
干预措施: Placebo (PLA) + MTX, DB (Drug)
Placebo + MTX switched to abatacept + MTX (DB)
Participants received placebo plus methotrexate for days 1-197, and abatacept plus methotrexate for days 198-365
干预措施: PLA + MTX switched to ABA+ MTX, DB (Drug)
Abatacept (open-label)
Days 365 to 729 All participants receive Active Drug
干预措施: ABA, open-label (OL) (Drug)
结局指标
主要结局
OL; Mean Change From Baseline to Day 365 in Hematocrit
时间窗: Baseline (Day 1), Day 365
Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 365 in Platelets
时间窗: Baseline (Day 1), Day 365
Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, and AEs Leading to Discontinuation
时间窗: From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months)
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this 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.
OL; Mean Change From Baseline to Day 365 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase
时间窗: Baseline (Day 1), Day 365
alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
DB; Adjusted Mean Change From Baseline to Day 197 in Disease Activity Score (DAS) 28 Score (Erythrocyte Sedimentation Rate [ESR]) For ABA Versus PLA (Last Observation Carried Forward [LOCF] Analysis)
时间窗: Baseline (Day 1), 6 months (Day 197)
The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or C-reactive protein (CRP), and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). A clinically significant response is a decrease in DAS28 score of \>1.2 from baseline.
OL; Mean Change From Baseline to Day 729 in White Blood Cells
时间窗: Baseline (Day 1), Day 729
Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 729 in Electrolytes
时间窗: Baseline (Day 1), Day 729
Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 729 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid
时间窗: Baseline (Day 1), Day 729
Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Change From Baseline to Day 729 in Hemoglobin, Total Protein, and Albumin
时间窗: Baseline (Day 1), Day 729
Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Number of Participants With AEs of Special Interest
时间窗: From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months)
AE=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 are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, autoimmune disorders; malignancies; and acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion).
OL; Number of Participants With Select Hematologic Laboratory Abnormalities
时间窗: From Day 366 through end of OL (range from 1.9 months to 42.3 months)
High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Hemoglobin (HGB): \>3 g/dL decrease from Baseline (BL); Hematocrit: \<0.75 x BL; Erythrocytes: \<0.75 x BL; Platelets (PLT): \<0.67 x LLN/\>1.5 x ULN; Leukocytes: \<0.75 x LLN/ \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; lymphocytes: \<0.750 x 10\^3 c/uL/ \>7.50 x 10\^3 c/uL; monocytes: \>2000 mm3; eosinophils: \>0.750 x 10\^3 c/uL;
OL; Number of Participants With Select Blood Chemistry Laboratory Abnormalities
时间窗: From Day 366 through end of OL (range from 1.9 months to 42.3 months)
Low=lower than LLN, High=greater than ULN. LLN/ULN= Alkaline phosphatase (ALP): \>2 x ULN; aspartate aminotransferase (AST): \>3 x ULN; alanine aminotransferase (ALT): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL
OL; Mean Change From Baseline to Day 365 in Hemoglobin, Total Protein, and Albumin
时间窗: Baseline (Day 1), Day 365
Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 365 in Erythrocytes
时间窗: Baseline (Day 1), Day 365
Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 365 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid
时间窗: Baseline (Day 1), Day 365
Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Change From Baseline to Day 729 in Platelets
时间窗: Baseline (Day 1), Day 729
Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 729 in Hematocrit
时间窗: Baseline (Day 1), Day 729
Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 729 in Erythrocytes
时间窗: Baseline (Day 1), Day 729
Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1121 in Hemoglobin, Total Protein, and Albumin
时间窗: Baseline (Day 1), Day 1121
Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 365 in White Blood Cells
时间窗: Baseline (Day 1), Day 365
Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 365 in Electrolytes
时间窗: Baseline (Day 1), Day 365
Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 1121 in Platelets
时间窗: Baseline (Day 1), Day 1121
Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 1121 in Hematocrit
时间窗: Baseline (Day 1), Day 1121
Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 1121 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase
时间窗: Baseline (Day 1), Day 1121
alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Change From Baseline to Day 1513 in Hemoglobin, Total Protein, and Albumin
时间窗: Baseline (Day 1), Day 1513
Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 1513 in Erythrocytes
时间窗: Baseline (Day 1), Day 1513
Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in Electrolytes
时间窗: Baseline (Day 1), Day 1513
Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 729 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase
时间窗: Baseline (Day 1), Day 729
alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Change From Baseline to Day 1121 in White Blood Cells
时间窗: Baseline (Day 1), Day 1121
Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 1121 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid
时间窗: Baseline (Day 1), Day 1121
Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Change From Baseline to Day 1513 in Platelets
时间窗: Baseline (Day 1), Day 1513
Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 1513 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid
时间窗: Baseline (Day 1), Day 1513
Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Temperature (T) During Open Label Period
时间窗: Days 365, 729, 1121, and 1513
Temperature (T), units=degrees Celcius
OL; Mean Change From Baseline to Day 1121 in Erythrocytes
时间窗: Baseline (Day 1), Day 1121
Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in Hematocrit
时间窗: Baseline (Day 1), Day 1513
Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in White Blood Cells
时间窗: Baseline (Day 1), Day 1513
Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 1513 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase
时间窗: Baseline (Day 1), Day 1513
alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Heart Rate (HR) During Open Label Period
时间窗: Days 365, 729, 1121, and 1513
Heart Rate (HR), units=beats per minute (bpm)
OL; Mean Change From Baseline to Day 1121 in Electrolytes
时间窗: Baseline (Day 1), Day 1121
Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Systolic (SBP) and Diastolic (DBP) Blood Pressure During Open Label Period
时间窗: Days 365, 729, 1121, and 1513
Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), units=mm mercury (Hg)
次要结局
- DB; Adjusted Mean Change From Baseline to Day 197 in DAS 28 Score (ESR) For INF Versus PLA (LOCF Analysis)(Baseline (Day 1), 6 months (Day 197))
- DB; Adjusted Mean Change From Baseline to Day 197 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)(Baseline (Day 1), 6 months (Day 197))
- DB; Adjusted Mean Change From Baseline to Day 365 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)(Baseline (Day 1), 12 months (Day 365))
- DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 365(From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; DAS 28 (ESR) Area Under The Curve (AUC) Over 12 Months For ABA Versus INF(From Day 1 through Day 365 (12 months))
- DB; Adjusted Mean Change From Baseline to Day 197 in HAQ-DI (LOCF Analysis)(Baseline (Day 1), 6 months (Day 197))
- DB; Adjusted Mean Change From Baseline to Day 365 in HAQ-DI (LOCF Analysis)(Baseline (Day 1), 12 months (Day 365))
- DB; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) at Day 365(DB Day 365)
- DB; Number of Participants With AEs of Special Interest From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept(From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Significant Changes in Mean Heart Rate During Days 1 Through 197 and Days 1 Through 365(From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Percentage of Participants With Antibodies Against Infliximab (Human Anti-chimeric Antibody [HACA]) From Day 1 Through Day 365(Day 1 through day 365)
- OL; Mean Change From Baseline Over Time in DAS 28 (ESR) Score(Baseline (Day 1), Day 365, Day 533, Day 729)
- DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 197(DB Day 197)
- DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 365(DB Day 365)
- DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 365(From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 197(DB Day 197)
- DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 365(DB Day 365)
- DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 197(From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Significant Changes in Mean Temperature During Days 1 Through 197 and Days 1 Through 365(From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Anti-Abatacept Antibodies From Day 1 Through Day 365 (Electrochemiluminescent [ECL] Immunoassay)(Day 1 through day 365)
- OL; Percentage of Participants With American College of Rheumatology (ACR) Responses Over Time(DB Day 197, Day 365, Day 533, Day 729)
- OL; Percentage of Participants Who Achieved Major Clinical Response(Defined from the date of achieving ACR 70 response to 6 months post response)
- DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 197(From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 365(From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept(From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Significant Changes in Mean Systolic and Diastolic Blood Pressure During Days 1 Through 197 and Days 1 Through 365(From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study)
- DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 197(From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study)
- OL; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) Over Time(DB Days 365, 533, and 729)
- OL; Percentage of Participants With DAS28 (ESR) Remission and Low Disease Activity (LDAS) Over Time(Baseline (Day 1), Day 365, Day 533, Day 729)
- OL; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Over Time(OL Days 197, 253, 281, 309, 337, 365, 449, 533, 617, and 729)
- OL; Adjusted Mean Change From Baseline to Day 729 in HAQ-DI(Day 1 (Baseline), Day 729)