Juvenile Rheumatoid Arthritis
Conditions
Brief summary
The primary objective of this study was to determine the efficacy of etanercept in children with polyarticular course JRA.
Detailed description
This was a two-part study. In the first part of the study, all participants received open-label etanercept twice a week for 90 days. At the end of the 90 days, participants with disease response as defined by the JRA Definition of Improvement (DOI) using the JRA Core Set Criteria were randomized in part 2 of the study to receive placebo or continued administration of etanercept until either disease flare occurred or 4 months elapsed, whichever was earlier. Participants who did not meet the DOI at day 90, participants who had disease flare during part 2 and participants who completed the blinded part of the study were eligible to receive open-label treatment with etanercept under protocol 16.0018 (NCT00357903).
Interventions
DRUGEtanercept
Administered twice weekly by subcutaneous injection
DRUGPlacebo
Administered twice weekly by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of JRA by the American College of Rheumatology (ACR) criteria. * Disease course must be polyarticular with disease duration long enough to have been given an adequate trial of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose methotrexate at a dose of at least 10 mg/m²/week * Continuing active disease, defined as ≥ 5 swollen joints and ≥ 3 joints with limitation of motion accompanied by pain, tenderness or warmth. * Disease refractory to methotrexate or intolerant of methotrexate. * Have not received disease-modifying anti-rheumatic drugs (DMARDs) within 28 days prior to enrollment. * Have not received methotrexate within 14 days prior to dosing of study drug.
Exclusion criteria
* Pregnant or nursing female * Functional class IV by ACR criteria * Unable to meet concomitant medication restrictions * Intraarticular corticosteroid injection within 4 weeks prior to enrollment * Clinically significant deviations from normal, defined as: * 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 \> 2 times ULN * creatinine clearance \< 90 mL/min/1.73 m² body surface area (BSA) and/or a glomerular filtration rate (GFR) \< 90 mL/min/1.73 m² BSA. * known human immunodeficiency virus (HIV), hepatitis B surface antigen positivity, or hepatitis C positivity. * anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies or anti-cardiolipin antibodies present. * Previously received antibody to TNF, antibody to cluster of differentiation (CD)4, or diphtheria interleukin (IL)-2-fusion protein (DAB-IL-2) * Participated in a study of an investigational drug or biologic requiring informed consent within 3 months prior to study entry. * Any concurrent medical condition which would, in the investigator's opinion, compromise the patient's ability to tolerate the study drug or make the patient unable to cooperate with the protocol. * History of or current psychiatric illness that would interfere with ability to comply with protocol requirements or informed consent. * History or drug or alcohol abuse that would interfere with ability to comply with protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Flare in Part 2 | End of part 1 (day 90) and months 4 to 7 | Disease flare was defined as a 30% or greater worsening in three of the six JRA Core Set Criteria and ≥ 30% improvement in one or less of the six JRA Core Set Criteria compared to day 90 and a minimum of two active joints (joints with swelling or limitation of movement plus pain and/or tenderness). The JRA Core Set criteria consisted of: * Physician global assessment of disease severity assessed on a visual analog scale (VAS) from 0 (asymptomatic) to 10 (severe symptoms); * Patient/parent global assessment of overall well-being assesses on a VAS from 0 (asymptomatic) to 10 (severe symptoms); * Number of active joints; * Number of joints with limitation of motion (LOM) and with pain, tenderness, or both; * Childhood Health Assessment Questionnaire (CHAQ) disability domain; * Erythrocyte sedimentation rate (ESR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Flare in Part 2 | Months 4 to 7 | The time from day 90 to flare. Participants who withdrew without flare were censored at the time of withdrawal. |
| Number of Participants With Adverse Events | Part 1: 90 days (months 1-3) plus 30 days for participants who were not randomized into part 2. Part 2: From first dose of randomized treatment to 30 days after last dose (150 days; months 4-8). | — |
Participant flow
Recruitment details
Participants were enrolled at 9 sites in the United States and Canada. The study consisted of an open-label treatment period (part 1) where all participants received 0.4 mg etanercept twice weekly for 3 months, followed by a randomized double-blind treatment period (part 2).
Pre-assignment details
At the end of part 1 participants with disease response were randomized to part 2, with stratification according to study center and number of active joints (≤ 2 vs. \> 2) at the end of month 3.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Etanercept 0.4 mg/kg Participants received 0.4 mg/kg etanercept twice weekly for 90 days during Part 1. | 69 |
| Part 2: Placebo In Part 2 participants were randomized to receive placebo subcutaneous injection twice weekly for up to 4 months. | 26 |
| Part 2: Etanercept 0.4 mg/kg In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months. | 25 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1 | Adverse Event | 1 | 0 | 0 |
| Part 1 | Response Status | 2 | 0 | 0 |
| Part 1 | Withdrawal by Parent/Guardian | 1 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 1 | 0 | 0 |
| Part 2 | Response Status | 0 | 18 | 6 |
| Part 2 | Withdrawal by Parent/Guardian | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Part 1: Etanercept 0.4 mg/kg | Part 2: Placebo | Part 2: Etanercept 0.4 mg/kg |
|---|---|---|---|---|
| Age, Continuous Part 1 | 10.5 years STANDARD_DEVIATION 3.9 | 10.5 years STANDARD_DEVIATION 3.9 | — | — |
| Age, Continuous Part 2 | 10.6 years STANDARD_DEVIATION 3.9 | — | 12.2 years STANDARD_DEVIATION 3.5 | 8.9 years STANDARD_DEVIATION 3.7 |
| Age, Customized Part 1 13 - 17 years | 30 Participants | 30 Participants | — | — |
| Age, Customized Part 1 4 - 8 years | 25 Participants | 25 Participants | — | — |
| Age, Customized Part 1 9 - 12 years | 14 Participants | 14 Participants | — | — |
| Age, Customized Part 2 13 - 17 years | 24 Participants | — | 17 Participants | 7 Participants |
| Age, Customized Part 2 4 - 8 years | 18 Participants | — | 5 Participants | 13 Participants |
| Age, Customized Part 2 9 - 12 years | 9 Participants | — | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Part 1 Asian | 1 Participants | 1 Participants | — | — |
| Race/Ethnicity, Customized Part 1 Black | 6 Participants | 6 Participants | — | — |
| Race/Ethnicity, Customized Part 1 Hispanic | 9 Participants | 9 Participants | — | — |
| Race/Ethnicity, Customized Part 1 Native American | 1 Participants | 1 Participants | — | — |
| Race/Ethnicity, Customized Part 1 White | 52 Participants | 52 Participants | — | — |
| Race/Ethnicity, Customized Part 2 Asian | 1 Participants | — | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Part 2 Black | 4 Participants | — | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Part 2 Hispanic | 8 Participants | — | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Part 2 Native American | 1 Participants | — | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Part 2 White | 37 Participants | — | 23 Participants | 14 Participants |
| Sex: Female, Male Part 1 Female | 43 Participants | 43 Participants | — | — |
| Sex: Female, Male Part 1 Male | 26 Participants | 26 Participants | — | — |
| Sex: Female, Male Part 2 Female | 34 Participants | — | 15 Participants | 19 Participants |
| Sex: Female, Male Part 2 Male | 17 Participants | — | 11 Participants | 6 Participants |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 1 Pauciarticular | 7 Participants | 7 Participants | — | — |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 1 Polyarticular | 40 Participants | 40 Participants | — | — |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 1 Systemic | 22 Participants | 22 Participants | — | — |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 2 Pauciarticular | 3 Participants | — | 1 Participants | 2 Participants |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 2 Polyarticular | 31 Participants | — | 17 Participants | 14 Participants |
| Type of Onset of Juvenile Rheumatoid Arthritis (JRA) Part 2 Systemic | 17 Participants | — | 8 Participants | 9 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 | 59 / 69 | 12 / 26 | 19 / 25 |
| serious Total, serious adverse events | 1 / 69 | 0 / 26 | 1 / 25 |
Outcome results
Primary
Percentage of Participants With Disease Flare in Part 2
Disease flare was defined as a 30% or greater worsening in three of the six JRA Core Set Criteria and ≥ 30% improvement in one or less of the six JRA Core Set Criteria compared to day 90 and a minimum of two active joints (joints with swelling or limitation of movement plus pain and/or tenderness). The JRA Core Set criteria consisted of: * Physician global assessment of disease severity assessed on a visual analog scale (VAS) from 0 (asymptomatic) to 10 (severe symptoms); * Patient/parent global assessment of overall well-being assesses on a VAS from 0 (asymptomatic) to 10 (severe symptoms); * Number of active joints; * Number of joints with limitation of motion (LOM) and with pain, tenderness, or both; * Childhood Health Assessment Questionnaire (CHAQ) disability domain; * Erythrocyte sedimentation rate (ESR).
Time frame: End of part 1 (day 90) and months 4 to 7
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2: Placebo | Percentage of Participants With Disease Flare in Part 2 | 81 percentage of participants |
| Part 2: Etanercept 0.4 mg/kg | Percentage of Participants With Disease Flare in Part 2 | 28 percentage of participants |
p-value: 0.003Mantel Haenszel
Secondary
Number of Participants With Adverse Events
Time frame: Part 1: 90 days (months 1-3) plus 30 days for participants who were not randomized into part 2. Part 2: From first dose of randomized treatment to 30 days after last dose (150 days; months 4-8).
Population: All participants who received at least one dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 2: Placebo | Number of Participants With Adverse Events | Serious adverse events | 1 Participants |
| Part 2: Placebo | Number of Participants With Adverse Events | Infections | 43 Participants |
| Part 2: Placebo | Number of Participants With Adverse Events | Noninfectious adverse events | 51 Participants |
| Part 2: Placebo | Number of Participants With Adverse Events | Injection site reactions | 27 Participants |
| Part 2: Placebo | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Infections | 8 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Noninfectious adverse events | 9 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Injection site reactions | 1 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Serious adverse events | 1 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Noninfectious adverse events | 13 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Infections | 15 Participants |
| Part 2: Etanercept 0.4 mg/kg | Number of Participants With Adverse Events | Injection site reactions | 1 Participants |
Secondary
Time to Flare in Part 2
The time from day 90 to flare. Participants who withdrew without flare were censored at the time of withdrawal.
Time frame: Months 4 to 7
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: Placebo | Time to Flare in Part 2 | 28.0 days |
| Part 2: Etanercept 0.4 mg/kg | Time to Flare in Part 2 | 116.0 days |
p-value: 0.0001Log Rank