Clinical trial NCT00048542: Study of Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis (JIA)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arthritis, Juvenile Idiopathic
Keywords: Polyarticular Juvenile Idiopathic Arthritis
Lead sponsor: Abbott
Sponsor class: INDUSTRY
First posted: 2002-11-05
Enrollment: 171
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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this clinical trial was chosen to evaluate adalimumab in subjects who were either methotrexate (MTX)-naive or had been withdrawn from MTX at least 2 weeks prior to study drug administration (non-MTX stratum) or were inadequate responders to MTX and continued MTX treatment (MTX stratum).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

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Subjects in the Non-MTX Stratum With Disease Flare During the Double-Blind Phase
timeFrame: Week 16 to Week 48 (32 weeks)
Secondary outcomes:
measure: Number of Subjects Meeting Pediatric American College of Rheumatology 30% (PedACR30) Response Criteria at the End of the Open-Label Lead-In Phase
timeFrame: Week 16
measure: Number of Subjects in the MTX Stratum With Disease Flare During the Double-Blind Phase
timeFrame: Week 16 to Week 48 (32 Weeks)
measure: Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the Non-MTX Stratum
timeFrame: Week 16 to Week 48 (32 weeks)
measure: Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the MTX Stratum
timeFrame: Week 16 to Week 48 (32 weeks)
measure: Number of Subjects Meeting PedACR30 Response Criteria at the End of the Double-Blind Phase
timeFrame: Week 48
measure: Number of Subjects Meeting PedACR50 Response Criteria at the End of the Double-Blind Phase
timeFrame: Week 48
measure: Number of Subjects Meeting PedACR70 Response Criteria at the End of the Double-Blind Phase
timeFrame: Week 48
measure: Mean Change From Baseline in Physician's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
timeFrame: Baseline and Week 48
measure: Mean Change From Baseline in Parent's/Patient's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
timeFrame: Baseline and Week 48
measure: Mean Change From Baseline in C-Reactive Protein Levels at Week 48 of the Double-Blind Phase
timeFrame: Baseline and Week 48
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Body Surface Area Phase
timeFrame: Open-Label Lead-In Phase Baseline
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 56 of the Open-Label Extension Body Surface Area Phase
timeFrame: Week 56
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 104 of the Open-Label Extension Body Surface Area Phase
timeFrame: Week 104
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Fixed Dose Phase
timeFrame: Baseline
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 48 of the Open-Label Extension Fixed Dose Phase
timeFrame: Week 48
measure: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 112 of the Open-Label Extension Fixed Dose Phase
timeFrame: Week 112
measure: 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
timeFrame: Final Visit (up to 224 weeks of OLE FD phase)
Other outcomes:
measure: Baseline Measure: Gender, Female/Male - OLE BSA Phase
timeFrame: Baseline OLE BSA Phase
measure: Baseline Measure: Age Continuous - OLE BSA Phase
timeFrame: Baseline OLE BSA Phase
measure: Baseline Measure: Gender, Female/Male - OLE FD Phase
timeFrame: Baseline OLE FD Phase
measure: Baseline Measure: Age Continuous - OLE FD Phase
timeFrame: Baseline OLE FD Phase
Locations:
city: Birmingham
country: United States
facility: Site Ref # / Investigator 45524
state: Alabama
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 2235
state: California
city: Stanford
country: United States
facility: Site Reference ID/Investigator# 642
state: California
city: Delray Beach
country: United States
facility: Site Reference ID/Investigator# 638
state: Florida
city: St. Petersburg
country: United States
facility: Site Ref # / Investigator 45543
state: Florida
city: Chicago
country: United States
facility: Site Reference ID/Investigator# 640
state: Illinois
city: Kansas City
country: United States
facility: Site Reference ID/Investigator# 644
state: Kansas
city: Minneapolis
country: United States
facility: Site Reference ID/Investigator# 641
state: Minnesota
city: Omaha
country: United States
facility: Site Reference ID/Investigator# 645
state: Nebraska
city: Livingston
country: United States
facility: Site Reference ID/Investigator# 2501
state: New Jersey
city: New Hyde Park
country: United States
facility: Site Ref # / Investigator 45542
state: New York
city: Chapel Hill
country: United States
facility: Site Ref # / Investigator 45544
state: North Carolina
city: Columbus
country: United States
facility: Site Reference ID/Investigator# 386
state: Ohio
city: Salt Lake City
country: United States
facility: Site Ref # / Investigator 45525
state: Utah
city: Norfolk
country: United States
facility: Site Reference ID/Investigator# 406
state: Virginia
city: Ghent
country: Belgium
facility: Site Reference ID/Investigator# 621
city: Leuven
country: Belgium
facility: Site Reference ID/Investigator# 2538
city: Prague 2
country: Czech Republic
facility: Site Reference ID/Investigator# 518
city: Prague
country: Czech Republic
facility: Site Reference ID/Investigator# 519
city: Marseille Cedex 20
country: France
facility: Site Reference ID/Investigator# 45545
city: Paris
country: France
facility: Site Reference ID/Investigator# 516
city: Berlin
country: Germany
facility: Site Reference ID/Investigator# 627
city: Bremen
country: Germany
facility: Site Reference ID/Investigator# 625
city: Garmisch-Partenkirchen
country: Germany
facility: Site Ref # / Investigator 45522
city: Halle (Saale)
country: Germany
facility: Site Reference ID/Investigator# 628
city: Hamburg
country: Germany
facility: Site Reference ID/Investigator# 622
city: Genoa
country: Italy
facility: Site Reference ID/Investigator# 631
city: Milano
country: Italy
facility: Site Reference ID/Investigator# 636
city: Kosice
country: Slovakia
facility: Site Ref # / Investigator 45523
city: Piestany
country: Slovakia
facility: Site Reference ID/Investigator# 3425
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 3713
Study officials:
affiliation: Abbott
name: Laura Redden, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
citation: Horneff G, Seyger MMB, Arikan D, Kalabic J, Anderson JK, Lazar A, Williams DA, Wang C, Tarzynski-Potempa R, Hyams JS. Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease. J Pediatr. 2018 Oct;201:166-175.e3. doi: 10.1016/j.jpeds.2018.05.042. Epub 2018 Jul 25.
citation: Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A; Pediatric Rheumatology Collaborative Study Group; Pediatric Rheumatology International Trials Organisation. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008 Aug 21;359(8):810-20. doi: 10.1056/NEJMoa0706290.