Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Etanercept, Long-term Safety, Enbrel
Brief summary
This study was designed to provide all adult and pediatric arthritis patients (placebo and etanercept(TNFR:Fc) treated) who have participated in clinical trials with etanercept (TNFR:Fc) the opportunity to receive continued treatment with etanercept (TNFR:Fc). The primary objective of this study is to examine safety parameters.
Interventions
BIOLOGICALEtanercept
Adult Rheumatoid Arthritis (RA) patients on etanercept (TNFR:Fc) with well controlled arthritic symptoms will continue on the etanercept (TNFR:Fc) dose administered in their original protocol of enrollment. All other adults will receive 50 mg per week as two 25 mg subcutaneous (SC) injections at separate sites, either on the same day or 3 or 4 days apart. Pediatric patients ages 4 to 17 years will receive a 0.8 mg/kg per week dose (up to a maximum of 50 mg per week).
Sponsors
Immunex Corporation
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Previous enrollment in Immunex protocols * No clinically significant adverse events thought to be due to etanercept (TNFR:Fc) during previous treatment. * Negative serum pregnancy test not more than 14 days before the first dose of study drug in females of childbearing potential. * No more than one NSAID at a dose not greater than the maximum recommended dose and stable for at least two weeks prior to administration of etanercept (TNFR:Fc).
Exclusion criteria
- Previous receipt of TNFR:Fc (p55), antibody to TNF, anti-CD4 antibody, or diphtheria IL-2 fusion protein. * Receipt of investigational drugs or biologics (other than TNFR:Fc \[p75\]) within 1 month prior to the first dose of etanercept (TNFR:Fc) in this study. * Receipt of DMARDs or methotrexate (except patients from 16.0014) within two weeks prior to the first dose of etanercept (TNFR:Fc) in this study. * Receipt of cyclophosphamide within six months prior to the first dose of (etanercept (TNFR:Fc) in this study. * Receipt of cyclosporin within two weeks prior to the first dose of etanercept (TNFR:Fc) in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Exposure Adjusted Rate of Serious Adverse Events | Up to 10 years | Rate of serious adverse events adjusted to total exposure to etanercept (events / exposure \* 100) |
| Total Exposure to Etanercept With Gaps | Up to 10 years | Total participant exposure to etanercept (Enbrel) with gaps |
| Malignancy | Up to 10 years | Occurrence of one or more malignancies on study within 30 days of the last dose of etanercept |
| Total Exposure Adjusted Rate of Malignancies | Up to 10 years | Exposure-adjusted rate of malignancies, excluding nonmelanoma skin cancers, occurring on study within 30 days of the last dose of etanercept |
| Total Exposure Adjusted Rate of Deaths | Up to 10 years | Rate of deaths within 30 days of the last dose of etanercept, adjusted for total exposure to etanercept |
| Total Exposure Adjusted Rate of Serious Infectious Events | Up to 10 years | Exposure-adjusted rate of serious infectious events (associated with hospitalization or IV antibiotics) occurring on study within 30 days of the last dose of etanercept |
| Lymphoma | Up to 10 years | Occurrence of one or more lymphomas on study within 30 days of the last dose of etanercept |
| Total Exposure Adjusted Rate of Lymphomas | Up to 10 years | Rate of lymphomas occurring on study within 30 days of the last dose of etanercept, adjusted for total exposure to etanercept |
| Serious Infectious Event | Up to 10 years | Occurrence of one or more serious infectious events within the participant on study within 30 days of the last dose of study medication. A serious infectious event is a serious adverse event that is infectious. |
| Death | Up to 10 years | Occurrence of death on study within 30 days of the last dose of etanercept |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Swollen Joint Count | Month 12 | Number of swollen joints |
| Dosing Period | Up to 10 years | Duration of etanercept dosing |
| Health Assessment Questionnaire Disability Index | Month 12 | Health Assessment Questionnaire Disability Index (HAQ DI). This index is a weighted average of 24 items, each scored 0 (no difficulty) to 3 (unable to function). |
| Childhood Health Assessment Questionnaire | Month 12 | Childhood Health Assessment Questionnaire (CHAQ) disability index, having a range of 0 (no difficulty) to 3 (unable to do). |
| C-Reactive Protein | Month 12 | C-reactive protein at month 12 |
| ACR20 at Month 3 in Adults | Baseline and month 3 | American College of Rheumatology (ACR) 20, defined as a 20% improvement in both tender and swollen joints (78 joints) and a 20% improvement in 3 of 5 items (including physician and patient global assessments), in adults |
| JRA DOI 30 at Month 3 in Juveniles | Baseline and month 3 | Juvenile Rheumatoid Arthritis Definition of Improvement 30 (JRA DOI 30), defined as a 30% improvement from baseline in 3 of 6 items (including Childhood Health Assessment Questionnaire, disease severity, overall well-being, and erythrocyte sedimentation rate) and a worsening of \>30% in at most one of the remaining items. |
| Standardized Incidence Rate for All SEER Cancers | up to 10 years | Standardized incidence rate for all cancers tracked by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) system. |
| Tender Joint Count | Month 12 | Number of tender joints, as assessed by the investigator using criteria based on pressure and joint manipulation |
Participant flow
Recruitment details
Participants were enrolled from 31 July 1997 through 12 Oct 1999
Participants by arm
| Arm | Count |
|---|---|
| Pediatric Participants Pediatric participants with juvenile rheumatoid arthritis who received a maximum 50 mg dose of etanercept administered subcutaneously once weekly | 58 |
| Adult Participants Adult participants with rheumatoid arthritis treated with a maximum etanercept dose of 50 mg administered subcutaneously once weekly | 581 |
| Total | 639 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 87 | 4 |
| Overall Study | Completed month 12 only | 0 | 1 |
| Overall Study | Death | 33 | 0 |
| Overall Study | Lost to Follow-up | 23 | 4 |
| Overall Study | Other | 49 | 10 |
| Overall Study | Physician Decision | 39 | 5 |
| Overall Study | Protocol issues | 14 | 3 |
| Overall Study | Response status | 61 | 9 |
| Overall Study | Withdrawal by Subject | 57 | 7 |
Baseline characteristics
| Characteristic | Pediatric Participants | Adult Participants | Total |
|---|---|---|---|
| Age, Continuous | 11.02 Years STANDARD_DEVIATION 3.8 | 52.87 Years STANDARD_DEVIATION 12.03 | 49.07 Years STANDARD_DEVIATION 16.66 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participant | 4 Participant | 5 Participant |
| Race/Ethnicity, Customized Asian | 1 Participant | 10 Participant | 11 Participant |
| Race/Ethnicity, Customized Black or African American | 4 Participant | 18 Participant | 22 Participant |
| Race/Ethnicity, Customized Hispanic or Latino | 9 Participant | 25 Participant | 34 Participant |
| Race/Ethnicity, Customized Other | 0 Participant | 2 Participant | 2 Participant |
| Race/Ethnicity, Customized White or Caucasian | 43 Participant | 522 Participant | 565 Participant |
| Sex: Female, Male Female | 39 Participants | 465 Participants | 504 Participants |
| Sex: Female, Male Male | 19 Participants | 116 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 484 / 581 | 49 / 58 |
| serious Total, serious adverse events | 293 / 581 | 16 / 58 |
Outcome results
Primary
Death
Occurrence of death on study within 30 days of the last dose of etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Death | 23 Participants |
| Pediatric Participants | Death | 0 Participants |
Primary
Lymphoma
Occurrence of one or more lymphomas on study within 30 days of the last dose of etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Lymphoma | 6 Participants |
| Pediatric Participants | Lymphoma | 0 Participants |
Primary
Malignancy
Occurrence of one or more malignancies on study within 30 days of the last dose of etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Malignancy | 48 Participants |
| Pediatric Participants | Malignancy | 0 Participants |
Primary
Serious Infectious Event
Occurrence of one or more serious infectious events within the participant on study within 30 days of the last dose of study medication. A serious infectious event is a serious adverse event that is infectious.
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Serious Infectious Event | 114 Participants |
| Pediatric Participants | Serious Infectious Event | 8 Participants |
Primary
Total Exposure Adjusted Rate of Deaths
Rate of deaths within 30 days of the last dose of etanercept, adjusted for total exposure to etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure Adjusted Rate of Deaths | 0.57 Deaths per 100 participant-years |
| Pediatric Participants | Total Exposure Adjusted Rate of Deaths | 0.00 Deaths per 100 participant-years |
Primary
Total Exposure Adjusted Rate of Lymphomas
Rate of lymphomas occurring on study within 30 days of the last dose of etanercept, adjusted for total exposure to etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure Adjusted Rate of Lymphomas | 0.15 Lymphomas per 100 participant-years |
| Pediatric Participants | Total Exposure Adjusted Rate of Lymphomas | 0.00 Lymphomas per 100 participant-years |
Primary
Total Exposure Adjusted Rate of Malignancies
Exposure-adjusted rate of malignancies, excluding nonmelanoma skin cancers, occurring on study within 30 days of the last dose of etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure Adjusted Rate of Malignancies | 1.41 Malignancies per 100 participant-years |
| Pediatric Participants | Total Exposure Adjusted Rate of Malignancies | 0.00 Malignancies per 100 participant-years |
Primary
Total Exposure Adjusted Rate of Serious Adverse Events
Rate of serious adverse events adjusted to total exposure to etanercept (events / exposure \* 100)
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure Adjusted Rate of Serious Adverse Events | 20.95 Events per 100 participant-years |
| Pediatric Participants | Total Exposure Adjusted Rate of Serious Adverse Events | 12.87 Events per 100 participant-years |
Primary
Total Exposure Adjusted Rate of Serious Infectious Events
Exposure-adjusted rate of serious infectious events (associated with hospitalization or IV antibiotics) occurring on study within 30 days of the last dose of etanercept
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure Adjusted Rate of Serious Infectious Events | 5.18 Events per 100 participant-years |
| Pediatric Participants | Total Exposure Adjusted Rate of Serious Infectious Events | 3.22 Events per 100 participant-years |
Primary
Total Exposure to Etanercept With Gaps
Total participant exposure to etanercept (Enbrel) with gaps
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Total Exposure to Etanercept With Gaps | 4033.07 Participant-years |
| Pediatric Participants | Total Exposure to Etanercept With Gaps | 341.98 Participant-years |
Secondary
ACR20 at Month 3 in Adults
American College of Rheumatology (ACR) 20, defined as a 20% improvement in both tender and swollen joints (78 joints) and a 20% improvement in 3 of 5 items (including physician and patient global assessments), in adults
Time frame: Baseline and month 3
Population: All participants who received at least one dose of etanercept and had available data at both baseline and month 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | ACR20 at Month 3 in Adults | 372 Participants |
Secondary
Childhood Health Assessment Questionnaire
Childhood Health Assessment Questionnaire (CHAQ) disability index, having a range of 0 (no difficulty) to 3 (unable to do).
Time frame: Month 12
Population: All participants who received at least one dose of etanercept and had available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | Childhood Health Assessment Questionnaire | 1.08 Units on a scale | Standard Deviation 0.95 |
Secondary
C-Reactive Protein
C-reactive protein at month 12
Time frame: Month 12
Population: All participants who received at least one dose of etanercept and had available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | C-Reactive Protein | 1.37 mg/dL | Standard Deviation 1.85 |
| Pediatric Participants | C-Reactive Protein | 2.11 mg/dL | Standard Deviation 3.82 |
Secondary
Dosing Period
Duration of etanercept dosing
Time frame: Up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | Dosing Period | 2535.4 Days | Standard Deviation 1433.77 |
| Pediatric Participants | Dosing Period | 2153.6 Days | Standard Deviation 1379.15 |
Secondary
Health Assessment Questionnaire Disability Index
Health Assessment Questionnaire Disability Index (HAQ DI). This index is a weighted average of 24 items, each scored 0 (no difficulty) to 3 (unable to function).
Time frame: Month 12
Population: All participants who received at least one dose of etanercept and had available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | Health Assessment Questionnaire Disability Index | 0.96 Units on a scale | Standard Deviation 0.71 |
Secondary
JRA DOI 30 at Month 3 in Juveniles
Juvenile Rheumatoid Arthritis Definition of Improvement 30 (JRA DOI 30), defined as a 30% improvement from baseline in 3 of 6 items (including Childhood Health Assessment Questionnaire, disease severity, overall well-being, and erythrocyte sedimentation rate) and a worsening of \>30% in at most one of the remaining items.
Time frame: Baseline and month 3
Population: All participants who received at least one dose of etanercept and were evaluable for this endpoint at 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | JRA DOI 30 at Month 3 in Juveniles | 46 Participants |
Secondary
Standardized Incidence Rate for All SEER Cancers
Standardized incidence rate for all cancers tracked by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) system.
Time frame: up to 10 years
Population: All participants who received at least one dose of etanercept
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Participants | Standardized Incidence Rate for All SEER Cancers | 1.30 Observed count / expected count |
| Pediatric Participants | Standardized Incidence Rate for All SEER Cancers | 0.00 Observed count / expected count |
95% CI: [0, 53.87]
95% CI: [0.97, 1.71]
Secondary
Swollen Joint Count
Number of swollen joints
Time frame: Month 12
Population: All participants who received at least one dose of etanercept and had available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | Swollen Joint Count | 9.14 Joints | Standard Deviation 8.83 |
| Pediatric Participants | Swollen Joint Count | 11.93 Joints | Standard Deviation 11.86 |
Secondary
Tender Joint Count
Number of tender joints, as assessed by the investigator using criteria based on pressure and joint manipulation
Time frame: Month 12
Population: All participants who received at least one dose of etanercept and had available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Participants | Tender Joint Count | 9.55 Joints | Standard Deviation 10.97 |
| Pediatric Participants | Tender Joint Count | 11.60 Joints | Standard Deviation 10.61 |