Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, RA, Infliximab, TA-650, Remicade
Brief summary
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.
Interventions
DRUGTA-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.
DRUGTA-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.
DRUGTA-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.
Sponsors
Tanabe Pharma Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Numeric Index of American College of Rheumatology Response (ACR-N, N Shows the Percent Improvement) | baseline and week 54 | The ACR-N index of improvement is the minimum of the following: (1) the percent decrease from baseline in tender joint counts(TJC) or (2) the percent decrease from baseline in swollen joint counts(SJC) or (3) the median percent decrease from baseline for the following: a. Patient's assessment of pain (visual analog scale (VAS) 0-100, 100 worst pain); b. Patient's global assessment of disease activity (VAS 0-100); c. Physician's global assessment of disease activity (VAS 0-100); d. Physical function as measured by the Health Assessment Questionnaire(HAQ)(0-3); e. C-Reactive Protein(CRP) measurement. Higher numbers (maximum:100) indicate more improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tender Joint Counts (TJC) | 54 weeks | 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) | 54 weeks | 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 | 54 weeks | 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 | baseline and week 54 | 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. |
| Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | 54 weeks | 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 \[0, no difficulty to 3, inability to perform a task\]; \[CRP\]) |
| Change in Modified Total Sharp Score (mTSS) at week54 From Baseline | baseline and week 54 | 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 | 54 weeks | 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 | 54 weeks | ATI (antibody to Infliximab) was measured by a modification of an enzyme immunoassay. |
| Change From Baseline to Week 54 in HAQ | 54 weeks | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TA-650 3 mg/kg 99 patients received TA-650 at 3mg/kg treatment during the double-blind period starting from week14. | 99 |
| TA-650 6 mg/kg 104 patients received TA-650 at 6mg/kg treatment during the double-blind period starting from week14. | 104 |
| TA-650 10 mg/kg 104 patients received TA-650 at 10mg/kg treatment during the double-blind period starting from week14. | 104 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Period | Adverse Event | 8 | 9 | 6 | 0 |
| Double-blind Period | Lack of Efficacy | 4 | 3 | 2 | 0 |
| Double-blind Period | not come to a hospital. | 0 | 1 | 0 | 0 |
| Double-blind Period | Withdrawal by Subject | 1 | 0 | 1 | 0 |
| Open-label Period | Adverse Event | 0 | 0 | 0 | 16 |
| Open-label Period | not come to a hospital | 0 | 0 | 0 | 1 |
| Open-label Period | Withdrawal by Subject | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | TA-650 3 mg/kg | TA-650 6 mg/kg | TA-650 10 mg/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 8 Participants | 12 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 89 Participants | 96 Participants | 92 Participants | 277 Participants |
| Age, Continuous | 49.7 years STANDARD_DEVIATION 11.7 | 48.8 years STANDARD_DEVIATION 11.8 | 50.4 years STANDARD_DEVIATION 12.5 | 49.6 years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 78 Participants | 86 Participants | 89 Participants | 253 Participants |
| Sex: Female, Male Male | 21 Participants | 18 Participants | 15 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 93 / 99 | 93 / 104 | 96 / 104 | 153 / 327 |
| serious Total, serious adverse events | 7 / 99 | 5 / 104 | 9 / 104 | 17 / 327 |
Outcome results
Primary
Numeric Index of American College of Rheumatology Response (ACR-N, N Shows the Percent Improvement)
The ACR-N index of improvement is the minimum of the following: (1) the percent decrease from baseline in tender joint counts(TJC) or (2) the percent decrease from baseline in swollen joint counts(SJC) or (3) the median percent decrease from baseline for the following: a. Patient's assessment of pain (visual analog scale (VAS) 0-100, 100 worst pain); b. Patient's global assessment of disease activity (VAS 0-100); c. Physician's global assessment of disease activity (VAS 0-100); d. Physical function as measured by the Health Assessment Questionnaire(HAQ)(0-3); e. C-Reactive Protein(CRP) measurement. Higher numbers (maximum:100) indicate more improvement.
Time frame: baseline and week 54
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TA-650 3 mg/kg | Numeric Index of American College of Rheumatology Response (ACR-N, N Shows the Percent Improvement) | 51.3 percent change | Standard Deviation 32.1 |
| TA-650 6 mg/kg | Numeric Index of American College of Rheumatology Response (ACR-N, N Shows the Percent Improvement) | 53.8 percent change | Standard Deviation 34.4 |
| TA-650 10 mg/kg | Numeric Index of American College of Rheumatology Response (ACR-N, N Shows the Percent Improvement) | 58.3 percent change | Standard Deviation 31.3 |
Secondary
Change From Baseline in DAS28
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.
Time frame: baseline and week 54
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TA-650 3 mg/kg | Change From Baseline in DAS28 | -2.30 units on a scale | Standard Deviation 1.56 |
| TA-650 6 mg/kg | Change From Baseline in DAS28 | -2.57 units on a scale | Standard Deviation 1.69 |
| TA-650 10 mg/kg | Change From Baseline in DAS28 | -2.80 units on a scale | Standard Deviation 1.58 |
Secondary
Change From Baseline to Week 54 in HAQ
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.
Time frame: 54 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TA-650 3 mg/kg | Change From Baseline to Week 54 in HAQ | -0.48 units on a scale | Standard Deviation 0.7 |
| TA-650 6 mg/kg | Change From Baseline to Week 54 in HAQ | -0.56 units on a scale | Standard Deviation 0.64 |
| TA-650 10 mg/kg | Change From Baseline to Week 54 in HAQ | -0.59 units on a scale | Standard Deviation 0.63 |
Secondary
Change in Modified Total Sharp Score (mTSS) at week54 From Baseline
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.
Time frame: baseline and week 54
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TA-650 3 mg/kg | Change in Modified Total Sharp Score (mTSS) at week54 From Baseline | 0.00 score |
| TA-650 6 mg/kg | Change in Modified Total Sharp Score (mTSS) at week54 From Baseline | 0.48 score |
| TA-650 10 mg/kg | Change in Modified Total Sharp Score (mTSS) at week54 From Baseline | 0.00 score |
Secondary
CRP Level
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.
Time frame: 54 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TA-650 3 mg/kg | CRP Level | CRP level, baseline | 2.5 mg/dl |
| TA-650 3 mg/kg | CRP Level | CRP level, week 54 | 0.5 mg/dl |
| TA-650 6 mg/kg | CRP Level | CRP level, baseline | 2.3 mg/dl |
| TA-650 6 mg/kg | CRP Level | CRP level, week 54 | 0.4 mg/dl |
| TA-650 10 mg/kg | CRP Level | CRP level, baseline | 2.3 mg/dl |
| TA-650 10 mg/kg | CRP Level | CRP level, week 54 | 0.2 mg/dl |
Secondary
Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70)
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 \[0, no difficulty to 3, inability to perform a task\]; \[CRP\])
Time frame: 54 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TA-650 3 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR50% improvement (percentage) | 60.6 percentage of participants |
| TA-650 3 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR20% improvement(percentage) | 75.8 percentage of participants |
| TA-650 3 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR70% improvement (percentage) | 37.4 percentage of participants |
| TA-650 6 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR50% improvement (percentage) | 58.7 percentage of participants |
| TA-650 6 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR20% improvement(percentage) | 78.8 percentage of participants |
| TA-650 6 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR70% improvement (percentage) | 42.3 percentage of participants |
| TA-650 10 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR20% improvement(percentage) | 82.7 percentage of participants |
| TA-650 10 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR70% improvement (percentage) | 43.3 percentage of participants |
| TA-650 10 mg/kg | Percentage of Participants Achieving American College of Rheumatology 20, 50 and 70% Response (ACR20, 50, 70) | ACR50% improvement (percentage) | 66.3 percentage of participants |
Secondary
Pharmacokinetics Positive- ATI
ATI (antibody to Infliximab) was measured by a modification of an enzyme immunoassay.
Time frame: 54 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TA-650 3 mg/kg | Pharmacokinetics Positive- ATI | 27 participants |
| TA-650 6 mg/kg | Pharmacokinetics Positive- ATI | 24 participants |
| TA-650 10 mg/kg | Pharmacokinetics Positive- ATI | 13 participants |
Secondary
Pharmacokinetics- Serum Concentration of Infliximab
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.
Time frame: 54 weeks
Secondary
Swollen Joint Count (SJC)
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.
Time frame: 54 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TA-650 3 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, baseline | 14.2 count | Standard Deviation 6.1 |
| TA-650 3 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, week 54 | 3.6 count | Standard Deviation 4.8 |
| TA-650 6 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, baseline | 13.1 count | Standard Deviation 8.4 |
| TA-650 6 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, week 54 | 3.3 count | Standard Deviation 4.6 |
| TA-650 10 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, baseline | 13.7 count | Standard Deviation 7.3 |
| TA-650 10 mg/kg | Swollen Joint Count (SJC) | Swollen joint count, week 54 | 3.0 count | Standard Deviation 4.6 |
Secondary
Tender Joint Counts (TJC)
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.
Time frame: 54 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TA-650 3 mg/kg | Tender Joint Counts (TJC) | Tender joint count, baseline | 18.6 count | Standard Deviation 11.3 |
| TA-650 3 mg/kg | Tender Joint Counts (TJC) | Tender joint count, week54 | 6.3 count | Standard Deviation 8.6 |
| TA-650 6 mg/kg | Tender Joint Counts (TJC) | Tender joint count, baseline | 18.0 count | Standard Deviation 10.5 |
| TA-650 6 mg/kg | Tender Joint Counts (TJC) | Tender joint count, week54 | 4.8 count | Standard Deviation 7.7 |
| TA-650 10 mg/kg | Tender Joint Counts (TJC) | Tender joint count, baseline | 17.5 count | Standard Deviation 10.9 |
| TA-650 10 mg/kg | Tender Joint Counts (TJC) | Tender joint count, week54 | 4.8 count | Standard Deviation 7.6 |