Study of Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis (JIA)

Arthritis, Juvenile Idiopathic Clinical Trial

Official title:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00048542
• Other study ID #: DE038
• Status: Completed
• Phase: Phase 3
• First received: November 1, 2002
• Last updated: August 18, 2011
• Start date: September 2002
• Est. completion date: June 2010

Study information

• Verified date: August 2011
• Source: Abbott
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationGermany: Federal Institute for Drugs and Medical DevicesCzech Republic: State Institute for Drug ControlItaly: Ministry of HealthFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Spain: Ministry of Health and ConsumptionSlovakia: State Institute for Drug Control
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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this clinical trial was chosen to evaluate adalimumab in subjects who were either methotrexate (MTX)-naive or had been withdrawn from MTX at least 2 weeks prior to study drug administration (non-MTX stratum) or were inadequate responders to MTX and continued MTX treatment (MTX stratum).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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 171
• Est. completion date: June 2010
• Est. primary completion date: January 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 4 Years to 17 Years

Eligibility

Inclusion Criteria:

• Subjects must have a diagnosis of polyarticular juvenile idiopathic arthritis (JIA) age 4 to 17 by the American College of Rheumatology (ACR) criteria. Disease onset may have been systemic, polyarticular, or pauciarticular. If the disease was systemic onset, then the subjects must be free of any systemic JIA manifestations for at least 3 months before the time of qualification.

• At the time of study screening, the subject must have continuing active disease defined as >= 5 swollen joints and >= 3 joints with limitation of motion (LOM). These joints are not mutually exclusive.

• Subjects may be either naïve to MTX, inadequate responders to MTX, or intolerant to MTX. Intolerance to MTX will be defined by the subject's physician. The MTX must be maintained at a dose of at least 10 mg/m2 body surface area/week for a minimum of 3 months, prior to screening.

• Duration of disease is not limited, but must have been long enough for a subject to have been given an adequate trial of nonsteroidal anti-inflammatory drugs (NSAIDs).

• Have not received other disease-modifying anti-rheumatic drugs (DMARDs) including penicillamine, hydroxychloroquine, sulfasalazine, oral or injectable gold, cyclosporin; or intravenous immunoglobulin (IV Ig); or cytotoxic agents, for at least 4 weeks prior to receiving 1st dose of study drug. Subjects currently on one or more of these DMARDs must demonstrate active disease (defined above) prior to a minimum 4 weeks (28 days) washout of all DMARDs.

• Subjects who are refractory to MTX after 3 months of treatment must demonstrate active disease (defined above) prior to enrollment in the open-label part of the trial.

• Have not received an intra-articular glucocorticoid injection within 4 weeks (28 days) prior to enrollment into the study.

• Have good venous access and stable hematocrit >= 24%.

• All sexually active male and female study participants must be practicing adequate contraception. Post-pubertal females must have a negative serum pregnancy test no greater than 10 days prior to the first dose of study drug.

• Parent or guardian has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject's parent or legal guardian has had the opportunity to ask questions.

Exclusion Criteria:

• Pregnant or nursing female.

• Functional class IV by ACR criteria.

• Laboratory parameters outside limits established in the protocol.

• Medical history, medical condition, or previous treatment not allowed by the protocol.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Juvenile
• Arthritis, Juvenile Idiopathic

Intervention

Biological:
• Double-Blind Adalimumab/Placebo + MTX
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.
• Double-Blind Adalimumab/Placebo
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.

Drug:
• OLE BSA Adalimumab +/- MTX
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.
• OLE FD Adalimumab +/- MTX
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.

Locations

Country	Name	City	State
Belgium	Site Reference ID/Investigator# 621	Ghent
Belgium	Site Reference ID/Investigator# 2538	Leuven
Czech Republic	Site Reference ID/Investigator# 519	Prague
Czech Republic	Site Reference ID/Investigator# 518	Prague 2
France	Site Reference ID/Investigator# 45545	Marseille Cedex 20
France	Site Reference ID/Investigator# 516	Paris
Germany	Site Reference ID/Investigator# 627	Berlin
Germany	Site Reference ID/Investigator# 625	Bremen
Germany	Site Ref # / Investigator 45522	Garmisch-Partenkirchen
Germany	Site Reference ID/Investigator# 628	Halle (Saale)
Germany	Site Reference ID/Investigator# 622	Hamburg
Italy	Site Reference ID/Investigator# 631	Genoa
Italy	Site Reference ID/Investigator# 636	Milano
Slovakia	Site Ref # / Investigator 45523	Kosice
Slovakia	Site Reference ID/Investigator# 3425	Piestany
Spain	Site Reference ID/Investigator# 3713	Madrid
United States	Site Ref # / Investigator 45524	Birmingham	Alabama
United States	Site Ref # / Investigator 45544	Chapel Hill	North Carolina
United States	Site Reference ID/Investigator# 640	Chicago	Illinois
United States	Site Reference ID/Investigator# 386	Columbus	Ohio
United States	Site Reference ID/Investigator# 638	Delray Beach	Florida
United States	Site Reference ID/Investigator# 644	Kansas City	Kansas
United States	Site Reference ID/Investigator# 2501	Livingston	New Jersey
United States	Site Reference ID/Investigator# 2235	Los Angeles	California
United States	Site Reference ID/Investigator# 641	Minneapolis	Minnesota
United States	Site Ref # / Investigator 45542	New Hyde Park	New York
United States	Site Reference ID/Investigator# 406	Norfolk	Virginia
United States	Site Reference ID/Investigator# 645	Omaha	Nebraska
United States	Site Ref # / Investigator 45525	Salt Lake City	Utah
United States	Site Ref # / Investigator 45543	St. Petersburg	Florida
United States	Site Reference ID/Investigator# 642	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Abbott

Countries where clinical trial is conducted

United States,  Belgium,  Czech Republic,  France,  Germany,  Italy,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Week 16 to Week 48 (32 weeks)	No
Secondary	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.	Week 16	No
Secondary	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.	Week 16 to Week 48 (32 Weeks)	No
Secondary	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.	Week 16 to Week 48 (32 weeks)	No
Secondary	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.	Week 16 to Week 48 (32 weeks)	No
Secondary	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.	Week 48	No
Secondary	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.	Week 48	No
Secondary	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.	Week 48	No
Secondary	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.	Baseline and Week 48	No
Secondary	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.	Baseline and Week 48	No
Secondary	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.	Baseline and Week 48	No
Secondary	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.	Open-Label Lead-In Phase Baseline	No
Secondary	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.	Week 56	No
Secondary	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.	Week 104	No
Secondary	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.	Baseline	No
Secondary	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.	Week 48	No
Secondary	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.	Week 112	No
Secondary	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).	Final Visit (up to 224 weeks of OLE FD phase)	No