This is a multicenter, Phase 3 randomized, placebo-controlled study designed to evaluate adalimumab in children 4 to 17 years old with polyarticular juvenile idiopathic arthritis (JIA) who are either methotrexate (MTX) treated or non-MTX treated.
The study design for this clinical trial was chosen to evaluate adalimumab in subjects who were either methotrexate (MTX)-naive or had been withdrawn from MTX at least 2 weeks prior to study drug administration (non-MTX stratum) or were inadequate responders to MTX and continued MTX treatment (MTX stratum). The study consisted of 4 phases: a 16-week Open-label Lead-in (OL LI), a 32-week Double-blind (DB) phase, an up to 136-week Open-label Extension Body Surface Area (OLE BSA) phase, and an up to 224-week OLE Fixed Dose (FD) phase. All subjects who met entry criteria were enrolled into one of the appropriate strata and received adalimumab (plus concomitant MTX in the MTX stratum) in the 16 week OL LI phase of the study. All subjects who responded to adalimumab during the OL LI phase were to be enrolled in the DB phase of the study and randomized to receive adalimumab (plus concomitant MTX in the MTX stratum) or placebo (plus concomitant MTX in the MTX stratum). Subjects in the DB phase received either adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose) or placebo subcutaneously (SC) administered every other week (eow). Adalimumab or placebo was administered for an additional 32 weeks or until flare of disease (based on PedACR30 response criteria = a worsening of 30% or more in 3 of the 6 response variables (Parent's global assessment of subject's overall well-being by visual analog scale \[VAS\], Physician's global assessment \[PhGA\] of subject's disease severity by VAS, number of active joints \[joints with swelling not due to deformity or joints with limitation of passive motion (LOM)\], pain, tenderness, or both, number of joints with LOM, Childhood Health Assessment Questionnaire \[CHAQ\], and CRP levels), a minimum of 2 active joints, and no more than 1 indicator improving by 30% or more), whichever occurred earlier. For subjects who did not have a disease flare, the DB phase was completed at Week 48. Subjects who experienced disease flare during the DB phase or subjects who completed 48 weeks of the study were given the option to receive adalimumab for up to a minimum of 44 weeks (up to a maximum of 136 weeks) in the OLE BSA phase before being eligible to switch to the OLE FD phase. In this phase, subjects received OL adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose SC eow). All subjects who completed at least 44 weeks of OLE BSA treatment were given the opportunity to continue into the OLE FD phase for up to 224 weeks of additional adalimumab exposure. In this phase, subjects weighing less than 30 kg were treated with a fixed dose of 20 mg of adalimumab SC eow. Subjects weighing 30 kg or more were treated with a fixed dose of 40 mg of adalimumab SC eow.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
171
Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) concomitantly with MTX treatment for 32 weeks during the Double-Blind phase. Total body dose of adalimumab was not to exceed 40 mg.
Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) without MTX treatment for 32 weeks during the Double-Blind Phase. Total body dose of adalimumab was not to exceed 40 mg.
Comparison of subcutaneous injection of 24 mg adalimumab per square meter of body surface area (BSA) every other week (eow) either with or without concomitant MTX treatment for a minimum of 44 weeks (up to a maximum of 136 weeks) during the Open-Label Extension BSA Phase.
Number of Subjects in the Non-MTX Stratum With Disease Flare During the Double-Blind Phase
The primary efficacy endpoint was the number of adalimumab-treated subjects in the non-MTX stratum with disease flare during the Double-Blind Phase compared with the number of placebo-treated subjects in the non-MTX stratum with disease flare during the double-blind phase. Subjects met the criteria for disease flare if they had 1) \>= 30% worsening in at least 3 of the 6 Juvenile Rheumatoid Arthritis (JRA) core set criteria and a minimum of 2 active joints, and 2) \>= 30% improvement in not more than 1 of the 6 JRA core set criteria.
Time frame: Week 16 to Week 48 (32 weeks)
Number of Subjects Meeting Pediatric American College of Rheumatology 30% (PedACR30) Response Criteria at the End of the Open-Label Lead-In Phase
Responders met the following criteria: \>= 30% improvement in \>= 3 of 6 JRA core set criteria, and \>= 30% worsening in not more than 1 JRA criterion, compared with the open-label baseline. JRA core set criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with limitation of motion \[LOM\] and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein.
Time frame: Week 16
Number of Subjects in the MTX Stratum With Disease Flare During the Double-Blind Phase
Subjects met criteria for disease flare if they had \>= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and \>= 30% improvement in not more than 1 JRA criterion. JRA core set criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein.
Time frame: Week 16 to Week 48 (32 Weeks)
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Comparison of adalimumab administered subcutaneously every other week (eow) either with or without concomitant MTX treatment for up to 224 weeks during the Open-Label Extension Fixed Dose (FD) Phase.
Site Ref # / Investigator 45524
Birmingham, Alabama, United States
Site Reference ID/Investigator# 2235
Los Angeles, California, United States
Site Reference ID/Investigator# 642
Stanford, California, United States
Site Reference ID/Investigator# 638
Delray Beach, Florida, United States
Site Ref # / Investigator 45543
St. Petersburg, Florida, United States
Site Reference ID/Investigator# 640
Chicago, Illinois, United States
Site Reference ID/Investigator# 644
Kansas City, Kansas, United States
Site Reference ID/Investigator# 641
Minneapolis, Minnesota, United States
Site Reference ID/Investigator# 645
Omaha, Nebraska, United States
Site Reference ID/Investigator# 2501
Livingston, New Jersey, United States
...and 21 more locations
Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the Non-MTX Stratum
A log rank test was performed and the Kaplan-Meier curve for time to disease flare from double-blind baseline (Week 16) to Week 48 was generated. Disease flare was defined as a \>= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and \>= 30% improvement in not more than 1 JRA criterion. The percentage of subjects without disease flare at each time point is presented.
Time frame: Week 16 to Week 48 (32 weeks)
Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the MTX Stratum
A log rank test was performed and the Kaplan-Meier curve for time to disease flare from double-blind baseline (Week 16) to Week 48 was generated. Disease flare was defined as a \>= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and \>= 30% improvement in not more than 1 JRA criterion. The percentage of subjects without disease flare at each time point is presented.
Time frame: Week 16 to Week 48 (32 weeks)
Number of Subjects Meeting PedACR30 Response Criteria at the End of the Double-Blind Phase
Responders met the following criteria: \>= 30% improvement in \>= 3 of 6 JIA core set criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core criteria are included in PedACR criteria.
Time frame: Week 48
Number of Subjects Meeting PedACR50 Response Criteria at the End of the Double-Blind Phase
Responders met the following criteria: \>= 50% improvement in \>= 3 of 6 JIA core set criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core variables are included in PedACR criteria.
Time frame: Week 48
Number of Subjects Meeting PedACR70 Response Criteria at the End of the Double-Blind Phase
Responders met the following criteria: \>= 70% improvement in \>= 3 of 6 JIA core set criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core variables are included in PedACR criteria.
Time frame: Week 48
Mean Change From Baseline in Physician's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
A 100 mm horizontal visual analog scale (VAS) was used to assess the Physician Global Assessment of Disease Activity. The left end of the VAS scale (0 mm) signified the absence of symptoms and the right end (100 mm) maximum disease activity. The mean change from open-label baseline to Week 48 was determined. Negative mean changes indicated improvement.
Time frame: Baseline and Week 48
Mean Change From Baseline in Parent's/Patient's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
A 100 mm horizontal visual analog scale (VAS) was used to assess the Parent's/Patient's Global Assessment of Disease Activity. The left end of the VAS (0 mm) signified the absence of symptoms and the right end (100 mm) maximum disease activity. The mean change from open-label baseline to Week 48 was determined. Negative mean changes indicated improvement.
Time frame: Baseline and Week 48
Mean Change From Baseline in C-Reactive Protein Levels at Week 48 of the Double-Blind Phase
Serum levels of C-reactive protein (CRP) were measured at screening (open-label baseline) and at Week 48. Negative mean changes in CRP from open-label baseline to Week 48 indicated improvement.
Time frame: Baseline and Week 48
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Body Surface Area Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Open-Label Lead-In Phase Baseline
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 56 of the Open-Label Extension Body Surface Area Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Week 56
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 104 of the Open-Label Extension Body Surface Area Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Week 104
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Fixed Dose Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL-LI baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Baseline
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 48 of the Open-Label Extension Fixed Dose Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL-LI baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Week 48
Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 112 of the Open-Label Extension Fixed Dose Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
Time frame: Week 112
Number of Subjects Meeting PedACR30/50/70 Response Criteria at the Final Visit (up to 224 Weeks) of the Open-Label Extension Fixed Dose Phase
Responders met the following criteria: \>= 30%/50%/70% improvement in \>= 3 of 6 JIA core criteria, and \>= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. Final Visit = last visit per subject (up to 224 weeks).
Time frame: Final Visit (up to 224 weeks of OLE FD phase)