Etanercept Plus Methotrexate Versus Methotrexate Alone in Children With Polyarticular Course Juvenile Rheumatoid Arthritis

Study Overview
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Brief Summary
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The primary objective of this study was to determine the efficacy of etanercept plus methotrexate vs methotrexate alone in pediatric patients with active polyarticular course juvenile rheumatoid arthritis (JRA).

Official Title
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A Phase III Double Blind Randomized Study Comparing Etanercept (Enbrel) Combined With Methotrexate vs Methotrexate Alone in Children With Polyarticular Course Juvenile Rheumatoid Arthritis

Conditions
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Juvenile Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Etanercept
* Drug: Placebo to Etanerceot
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have had a diagnosis of JRA by the American College of Rheumatology (ACR) criteria. Disease onset may have been systemic, polyarticular, or pauciarticular Disease course must have been polyarticular with at least 5 active joints Duration of disease was not limited, but must have been long enough for the patient to have been given a 3-month trial of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate at a dose between 0.3 and 1.0 mg/kg/week, orally (PO) or subcutaneously (SC) Receiving methotrexate at a dose between 0.3 mg/kg/wk and 1 mg/kg/wk at time of randomization. The dose of methotrexate must have been stable for one month prior to entry Patients may have failed prednisone, or been on a dosage of prednisone not to have exceeded 10 mg/day or 0.20 mg/kg/day (whichever was less) At the time of qualification (screening) for study and prior to wash-out of all disease modifying anti-rheumatic drugs (DMARDs), the patient must have had active disease, defined as ≥ 5 swollen joints accompanied by pain, and/or tenderness and/or warmth, and ≥ 3 joints with limitation of motion (LOM). (The joints with LOM may have been the same as those with swelling) Had good venous access and stable hematocrit ≥ 24 mL/dL Patients must have been pre-pubescent, or if post-pubertal at anytime during the study, and of child-bearing potential, must have been practicing adequate contraception Parent or legal guardian was able and willing to give informed consent Parent or legal guardian must have been willing to actively supervise storage and administration of study drug and ensure that the date and time of each dose was accurately recorded in the subject's diary Exclusion Criteria: Was unable to meet the concurrent medication restrictions as described in the protocol Pregnant or nursing female Patients were excluded if they demonstrated clinically significant deviations from normal (as defined below) in any of the following laboratory parameters: thrombocytopenia; platelet count < 100,000/cmm leukopenia; total white cell count < 4000 cells/cmm neutropenia; neutrophils < 1000 cells/cmm hepatic transaminase levels > two times the upper limit of normal (ULN) serum bilirubin > two times the ULN estimated creatinine clearance of < 90 mL/min/1.73 M² body surface area (BSA) known human immunodeficiency virus (HIV), hepatitis B surface antigen positivity not related to vaccination, or hepatitis C antibody positivity Had received etanercept, antibody to tumor necrosis factor (TNF) (i.e. infliximab or D2E7), antibody to cluster of differentiation (CD)4 (anti-CD4), diphtheria interleukin (IL)-2 fusion protein (DAB-IL-2) or leflunomide Had received DMARDs including D-penicillamine, hydroxychloroquine, sulfasalazine, oral or injectable gold, cyclosporin, azathioprine; intravenous immunoglobulin (IV Ig); or broadly immunosuppressant chemotherapeutic agents (e.g. cyclophosphamide, FK506, mycophenolate mofetil [CellCept]), for at least 28 days prior to enrollment and dosing of study drug. All DMARDs, other than methotrexate, must have been washed-out for a minimum of 28 days Had received intraarticular glucocorticoid injection within 28 days prior to enrollment on study Had previously received live virus vaccine within 3 months prior to study entry Had participated in a study of an investigational drug or biologic requiring informed-consent within three months prior to study entry Any concurrent medical condition which would have, in the investigator's opinion, compromised the patient's ability to tolerate the study drug or would have made the patient unable to cooperate with the protocol History of/or current psychiatric illness that would have interfered with ability to comply with protocol requirements or give informed consent Chronic or recurrent infections, or currently active infection at screening History of alcohol or drug abuse that would have interfered with ability to comply with protocol requirements Inability to have complied with the study requirements

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Methotrexate + Placebo<br>Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months. | Drug: Etanercept<br>* Administered by subcutaneous injection twice a week<br>* Other names: Enbrel;Drug: Placebo to Etanerceot<br>* Administered by subcutaneous injection twice a week<br>Drug: Methotrexate<br>* Administered orally or subcutaneously once a week at the same dose as prior to study entry<br>|
| Experimental: Methotrexate + Etanercept<br>Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months. | Drug: Etanercept<br>* Administered by subcutaneous injection twice a week<br>* Other names: Enbrel;Drug: Methotrexate<br>* Administered orally or subcutaneously once a week at the same dose as prior to study entry<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a JRA Response at Month 6 | Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 30% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR) | Baseline and month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a 50% Improvement in JRA DOI at Month 6 | Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 50% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR) | Baseline and month 6 | 
| Percentage of Participants With a 70% Improvement in JRA DOI at Month 6 | Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 70% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR) | Baseline and month 6 |