Efficacy and Safety of Increased Dose of TA-650(Infliximab) in Patients With Rheumatoid Arthritis

• Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  ACR 20 (50 or 70) response is a decrease of at least 20% (50% or 70%) in both TJC and SJC and in 3 to 5 assessments (patient's assessment of pain [VAS] with 0, no pain to 100, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity [0, very well to 100, very poor and 0, no arthritis activity to 100, extremely active, respectively]; [HAQ]: 20-questions on life activities [0, no difficulty to 3, inability to perform a task]; [CRP])
• Tender Joint Counts (TJC) [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  The TJC was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The TJC was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1.
• Swollen Joint Count (SJC) [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  The SJC was determined by examination of 66 joints and identifying when swelling was present. The SJC was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1.
• CRP Level [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation. Normal range of CRP is 0 mg/dL to 0.3 mg/dL. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.
• Change From Baseline in DAS28 [ Time Frame: baseline and week 54 ] [ Designated as safety issue: No ]
  DAS28 is calculated using TJC, SJC erythrocyte sedimentation rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x log (ESR) + 0.014 x Global Assessment of Arthritis where 28 joints are examined and a lower score indicates less disease activity. A negative change score indicates improvement. Total score range:0 to 9.4, higher score indicated more disease activity. DAS28 =<3.2 implied low disease activity, >3.2 to 5.1 implied moderate disease activity, >5.1 to 9.4 implied high disease activity and <2.6 implied remission.
• Change From Baseline to Week 54 in HAQ [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  HAQ: patient's assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
• Change in Modified Total Sharp Score (mTSS) at week54 From Baseline [ Time Frame: baseline and week 54 ] [ Designated as safety issue: No ]
  The mTSS is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 54 were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 and joint space narrowing on a scale of 0 (no damage) to 4. Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 390 [maximal disease]). An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.
• Pharmacokinetics- Serum Concentration of Infliximab [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  Serum level of infliximab was measured by enzyme-linked immunosorbent assay (ELISA), using a monoclonal antibody against infliximab. The lowest level of infliximab that could be reliably detected was 0.1 ug/ml.
• Pharmacokinetics Positive- ATI [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
  ATI (antibody to Infliximab) was measured by a modification of an enzyme immunoassay.

• ACR20, 50, 70% improvement, Tender joint counts and Swollen joint count, CRP, DAS28, HAQ and modified Sharp score [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]
• Safety: Adverse events, adverse drug reactions [ Time Frame: 54 weeks ] [ Designated as safety issue: Yes ]
• Pharmacokinetics- 1)Serum Concentration of Infliximab; and 2)Antibody to Infliximab（ATI) [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]

The purpose of this study is to assess the efficacy, safety and pharmacokinetics of maintenance treatment with 3mg/kg, 6mg/kg or 10mg/kg of TA-650 in combination with methotrexate (MTX) after three infusions (weeks-0, 2, 6) of 3mg/kg in Rheumatoid Arthritis (RA) showing an insufficient response to MTX.

• Drug: TA-650 3 mg/kg
  3 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 0, 2 and 6. Then 3 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 14, 22, 30, 38 and 46.
  Other Names:

  • Infliximab
  • REMICADE
• Drug: TA-650 6 mg/kg
  3 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 0, 2 and 6 weeks. Then 6 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 14, 22, 30, 38 and 46.
  Other Names:

  • Infliximab
  • REMICADE
• Drug: TA-650 10 mg/kg
  3 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 0, 2 and 6. Then 10 mg/kg of TA-650 will be intravenously infused over a period of more than 2 hours at weeks 14, 22, 30, 38 and 46.
  Other Names:

  • Infliximab
  • REMICADE

• Experimental: TA-650 3 mg/kg
  Intervention: Drug: TA-650 3 mg/kg
• Experimental: TA-650 6 mg/kg
  Intervention: Drug: TA-650 6 mg/kg
• Experimental: TA-650 10 mg/kg
  Intervention: Drug: TA-650 10 mg/kg

Inclusion Criteria:

• Patients with active RA in spite of stable dose of MTX

Exclusion Criteria:

• Having received infliximab in the past
• Having a history of serious infection which caused hospitalization within 6 months before the registration
• Having an active tuberculosis
• Having a complication or a history of malignancy within 5 years before the registration