Juvenile Rheumatoid Arthritis
Conditions
Brief summary
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).
Interventions
DRUGEtanercept
Administered by subcutaneous injection twice a week
DRUGPlacebo to Etanerceot
Administered by subcutaneous injection twice a week
DRUGMethotrexate
Administered orally or subcutaneously once a week at the same dose as prior to study entry
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a JRA Response at Month 6 | Baseline and 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a 50% Improvement in JRA DOI at Month 6 | Baseline and 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) |
| Percentage of Participants With a 70% Improvement in JRA DOI at Month 6 | Baseline and 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) |
Participant flow
Recruitment details
This study was conducted at 7 centers in the United States. The study consisted of a 6-month double-blind treatment period followed by a 6-month open-label period where all participants received etanercept + methotrexate. Early transition to open-label treatment was allowed after 2 months of blinded treatment, for disease flare or lack of response.
Pre-assignment details
Participants were randomized equally into 1 of 2 treatments for the double-blind portion of the study. Randomization was stratified by route of methotrexate administration (oral \[PO\] vs subcutaneous \[SC\]) prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate + Placebo 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. | 12 |
| Methotrexate + Etanercept 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. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Phase | Adverse Event | 0 | 1 |
| Double-blind Phase | Lack of Response | 6 | 2 |
| Double-blind Phase | Other | 1 | 3 |
| Open-label Phase | Other | 2 | 2 |
| Open-label Phase | Protocol Issues | 0 | 1 |
| Open-label Phase | Suboptimal Clinical Response | 1 | 0 |
Baseline characteristics
| Characteristic | Methotrexate + Placebo | Methotrexate + Etanercept | Total |
|---|---|---|---|
| Age, Continuous | 8.75 years STANDARD_DEVIATION 5.71 | 11.38 years STANDARD_DEVIATION 3.4 | 10.12 years STANDARD_DEVIATION 4.75 |
| Methotrexate Dosage Route Orally | 5 Participants | 6 Participants | 11 Participants |
| Methotrexate Dosage Route Subcutaneously | 7 Participants | 7 Participants | 14 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Oher | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 12 Participants |
| Type of Arthritis at Onset Pauciarticular | 1 Participants | 4 Participants | 5 Participants |
| Type of Arthritis at Onset Polyarticular | 7 Participants | 9 Participants | 16 Participants |
| Type of Arthritis at Onset Systemic | 4 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 12 | 12 / 13 | 15 / 19 |
| serious Total, serious adverse events | 1 / 12 | 1 / 13 | 0 / 19 |
Outcome results
Primary
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)
Time frame: Baseline and month 6
Population: All randomized participants; participants with missing data are counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate + Placebo | Percentage of Participants With a JRA Response at Month 6 | 33 percentage of participants |
| Methotrexate + Etanercept | Percentage of Participants With a JRA Response at Month 6 | 38 percentage of participants |
Secondary
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)
Time frame: Baseline and month 6
Population: All randomized participants; participants with missing data were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate + Placebo | Percentage of Participants With a 50% Improvement in JRA DOI at Month 6 | 25 percentage of participants |
| Methotrexate + Etanercept | Percentage of Participants With a 50% Improvement in JRA DOI at Month 6 | 38 percentage of participants |
Secondary
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)
Time frame: Baseline and month 6
Population: All randomized participants; participants with missing data were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate + Placebo | Percentage of Participants With a 70% Improvement in JRA DOI at Month 6 | 8 percentage of participants |
| Methotrexate + Etanercept | Percentage of Participants With a 70% Improvement in JRA DOI at Month 6 | 38 percentage of participants |