A Study of Tocilizumab in Patients With Active Polyarticular Juvenile Idiopathic Arthritis

JIA ACR30 flare is defined as a ≥ 30% worsening of 3 of 6 variables and no more than 1 of the remaining variables improving > 30%. The 6 variables are physician global assessment of disease activity (worsening of 20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (worsening of 20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew or who took escape medication are classified as flared. The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).

The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A higher score indicates more disease activity. A negative change score indicates improvement.

The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A higher score indicates poorer well-being. A negative change score indicates improvement.

Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.

Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.

Functional ability is assessed with the Childhood Health Assessment Questionnaire (CHAQ-DI) disability index which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement.

The JADAS-27 is derived from the following components: Physician's global assessment of disease activity on a 0-100 mm visual analog scale (VAS)/10, patient/parent's global assessment of overall well-being on a 0-100 mm VAS/10, normalized erythrocyte sedimentation rate (ESR) (if ESR is ≤ 20 then set to 0, if ≥ 120 then set to 10, and if > 20 and < 120 then apply formula [ESR-20]/10), and number of joints (maximum of 27) with active arthritis (cervical spine, left/right elbow, left/right wrist, left/right MCP1-3, left/right PIP1-5, left/right hips, left/right knee and left/right ankle). The scores for the first 3 components range from 0-10; the score for the final component ranges from 0-27. The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain.

A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10.

C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry.

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory.

Platelets were measured in blood samples taken from the patients.

White blood cells were measured in blood samples taken from the patients.

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.

The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A higher score indicates more disease activity. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A higher score indicates poorer well-being. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

The Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), as a measure of functional ability, consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.

The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward (LOCF) imputation for missing values. The analysis was adjusted for the randomization stratification factors background use of methotrexate and background use of oral corticosteroids, and the pain visual analog scale score at Baseline. The adjusted means from the fitted model are presented.

A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10.

The statistical test is not significant due to a break in the hierarchical chain of significance testing.

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Results are reported for the subgroups: Previous biologic treatment (yes/no), concomitant methotrexate use (yes/no), rheumatoid factor (positive/negative), concomitant oral corticosteroid use (yes/no). Last observation carried forward was applied to missing components at visits.

The JADAS-71 is composed of 4 components: Physician global assessment of disease activity on a visual analog scale (VAS) (range = 0-10, left end of the line = arthritis inactive, ie, symptom-free and no arthritis symptoms; right end = arthritis very active), patient/parent global assessment of overall well-being on a VAS (range = 0-10, left end of the line = very well, ie, symptom-free and no arthritis disease activity; right end = very poor, ie, maximum arthritis disease activity), normalized erythrocyte sedimentation rate (ESR) (range = 0-10, If ESR is ≤ 20 mm/h, set to 0. If ≥ 120 mm/h, set to 10 mm/h. If > 20 mm/h and < 120 mm/h, apply formula: [ESR - 20 mm/h]/10 mm/h), and a count of active arthritis (swelling present or pain present and limitation of motion) in 71 selected joints (range=0-71). The JADAS-71 is the sum of the 4 component scores and ranges from 0-101. A higher score indicates more arthritis disease activity. A positive change score indicates improvement.

The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A negative change score indicates improvement.

The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A negative change score indicates improvement.

Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.

Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.

Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.

Functional ability is assessed with the Childhood Health Assessment Questionnaire (CHAQ-DI) disability index which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A negative change score indicates improvement.

The CHAQ-DI consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A minimally important improvement is an improvement ≥ 0.13 over Baseline. Patients who withdrew due to non-safety reasons are classified as non-responders.

C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry.

The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain. A negative change score indicates improvement.

A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10. Patients who withdrew due to non-safety reasons are classified as non-responders.

A patient was in clinical remission if they had inactive disease at all visits in the 6 months prior to and including the visit assessment day. A patient was judged to have inactive disease if all of the following criteria were met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10. Patients who withdrew due to non-safety reasons are classified as non-responders.

A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew due to non-safety reasons are classified as non-responders.

Due to the different types of corticosteroid medications available, the prednisone equivalent was used in the calculation of the oral corticosteroid dose. Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.

Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.

The height Standard Deviation Score was calculated using the following formula: (Observed height - median of the reference population)/standard deviation of the reference population. The reference population was defined as that of the same sex and age to the nearest completed year and month using the World Health Organization norms. A negative score indicates less height than the reference population.