Rheumatoid Arthritis
Conditions
Keywords
Etanercept, Enbrel, DCE-MRI, RA
Brief summary
The purpose of this study is to assess whether DCE-MRI can detect changes of active disease in rheumatoid arthritis (RA) patients after 4, 8 and 12 weeks of etanercept.
Detailed description
The current literature shows the promise of magnetic resonance imaging (MRI) for assessing response to therapy in RA but the heterogeneity of the methodology and the semi-quantitative nature of the image analysis limits its applicability. To evaluate the ability of DCE-MRI to serve as a biomarker for treatment-induced changes in RA associated synovial inflammation, the reproducibility of the measurement and an effect size are required. Additional endpoints such as synovial volume, bone erosion progression and bone marrow edema-like changes may also prove useful for short-term assessment of a therapeutic intervention, but have not been explored in the context of a pharmacodynamic biomarker. It is therefore critical to conduct a carefully designed longitudinal study, focused on identifying the key parameters related to the instrumentation and data analysis, to fully evaluate the potential utility of MRI in an early clinical development setting. Importantly, this study will also demonstrate the feasibility of using DCE-MRI at multiple centers to acquire useful information that will drive program decisions. Expanded Access: Amgen provides expanded access for this clinical trial. Contact the Amgen Call Center (866-572-6436) for more information.
Interventions
DRUGEtanercept
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Fulfillment of the 1987 American College of Rheumatology (ACR) criteria for RA with a disease duration \> 6 months * Presence of active disease (defined as both tender and swollen joints) in at least one wrist * Sub-optimal response to methotrexate (MTX) defined by the presence of the following criteria (based on 68/66 joint count): 8 or more swollen joints AND 8 or more tender joints (with involvement of the wrist, fingers and at least one region outside the hands) at screening * Must be receiving MTX at a stable dose \> 15 mg/week at least 12 weeks prior to baseline * a lower dose is acceptable if otherwise not tolerated (toxicity documentation required).
Exclusion criteria
* Patients who are currently receiving disease modifying anti-rheumatic drug (DMARD) therapy (other than MTX, hydroxychloroquine or sulfasalazine) including tumor necrosis factor (TNF) antagonists (etanercept, infliximab, and adalimumab), abatacept, rituximab, leflunomide, cyclosporine, and gold (oral and intramuscular injection) within 8 weeks or 5.5 half-lives, whichever is longer, of screening * Co-existing condition requiring medications that alter vascular flow (e.g., nitrates, calcium channel blockers, ergot containing drugs) \[Potential effects of antihypertensive and migraine medications will be discussed with the Sponsor\] * Comorbid autoimmune disorders including systemic lupus erythematosus * Unable to undergo an MRI examination (e.g., presence of a pacemaker, defibrillator, or other implanted device such as anterior interbody cages, aneurysm clip or pedicle screws * allergic to contrast agent * tattoos \[in area of examination if contains metallic pigment\]) * or will likely require sedation for the procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-29 | Day 1 to Day 29 | Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 29. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
| Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-57 | Day 1 to Day 57 | Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 57. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
| Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-85 | Day 1 to Day 85 | Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 85. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, increases in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
| Percent Change in Synovial Initial Area Under the (Contrast-time) Curve (IAUC) From Days 1-29 | Day 1 to Day 29 | Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 29. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
| Percent Change in the Synovial Initial Area Under the Contrast-Tme Curve (IAUC) From Days 1-57 | Day 1 to Day 57 | Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 57. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
| Percent Change in the Synovial Initial Area Under the Contrast-Time Curve (IAUC) From Days 1-85 | Day 1 to Day 85 | Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 85. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 29 | Day -28 to Day 29 | Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 29 and from Day -28 to Day 1 |
| Percent Change in Synovial Volume From Days 1-29 | Day 1 to Day 29 | Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 29. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent. |
| Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 85 | Day -28 to Day 85 | Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 85 and from Day -28 to Day 1 |
| Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 57 | Day -28 to Day 57 | Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 57 and from Day -28 to Day 1 |
| Percent Change in Synovial Volume From Days 1-57 | Day 1 to Day 57 | Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 57. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent. |
| Percent Change in Synovial Volume From Days 1-85 | Day 1 to Day 85 | Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 85. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent. |
| Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 29 | Day -28 to Day 29 | Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 29 and from study day -28 to study day 1. |
| Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 57 | Day -28 to Day 57 | Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 57 and from study day -28 to study day 1. |
| Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 85 | Day -28 to Day 85 | Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 85 and from study day -28 to study day 1 |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from 13 December 2006 through 27 April 2009
Participants by arm
| Arm | Count |
|---|---|
| Etanercept Etanercept 50 mg administered by subcutaneous injection once weekly for up to 12 weeks. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Etanercept |
|---|---|
| Age Continuous | 50.6 Years STANDARD_DEVIATION 14.3 |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 8 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Percent Change in Synovial Initial Area Under the (Contrast-time) Curve (IAUC) From Days 1-29
Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 29. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 29
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Initial Area Under the (Contrast-time) Curve (IAUC) From Days 1-29 | 8.64 Percent change | Standard Deviation 59.65 |
Primary
Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-29
Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 29. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 29
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available Day 29 data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-29 | 15.04 Percent change | Standard Deviation 70.53 |
Primary
Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-57
Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 57. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 57
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-57 | 40.75 Percent change | Standard Deviation 77.28 |
Primary
Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-85
Percent change in transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from study day 1 to study day 85. Ktrans reflects contrast delivery (capillary blood flow) and transport across the vascular endothelium (capillary permeability-surface area product), with the dominant factor depending on whether delivery is flow or permeability limited. A Ktrans value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, increases in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 85
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Transfer Constant (Ktrans) From Days 1-85 | 55.00 Percent change | Standard Deviation 136.97 |
Primary
Percent Change in the Synovial Initial Area Under the Contrast-Time Curve (IAUC) From Days 1-85
Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 85. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 85
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in the Synovial Initial Area Under the Contrast-Time Curve (IAUC) From Days 1-85 | 34.54 Percent change | Standard Deviation 84.91 |
Primary
Percent Change in the Synovial Initial Area Under the Contrast-Tme Curve (IAUC) From Days 1-57
Percent change in the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 57. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Day 1 to Day 57
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in the Synovial Initial Area Under the Contrast-Tme Curve (IAUC) From Days 1-57 | 15.30 Percent change | Standard Deviation 33.98 |
Secondary
Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 29
Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 29 and from Day -28 to Day 1
Time frame: Day -28 to Day 29
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 29 | -5.96 percent change | Standard Deviation 126.57 |
Secondary
Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 57
Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 57 and from Day -28 to Day 1
Time frame: Day -28 to Day 57
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 57 | -8.68 percent change | Standard Deviation 127.57 |
Secondary
Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 85
Difference in percent change between the synovial initial area under the contrast-time curve (IAUC) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from Day 1 to Day 85 and from Day -28 to Day 1
Time frame: Day -28 to Day 85
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in IAUC From Days -28 to 1 and Days 1 to 85 | 10.55 percent change | Standard Deviation 146.25 |
Secondary
Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 29
Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 29 and from study day -28 to study day 1.
Time frame: Day -28 to Day 29
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 29 | -50.24 percent change | Standard Deviation 231.8 |
Secondary
Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 57
Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 57 and from study day -28 to study day 1.
Time frame: Day -28 to Day 57
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 57 | -49.96 percent change | Standard Deviation 265.51 |
Secondary
Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 85
Difference in percent change between synovial transfer constant (Ktrans) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from study day 1 to study day 85 and from study day -28 to study day 1
Time frame: Day -28 to Day 85
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Difference Between Percent Change in Ktrans From Days -28 to 1 and Days 1 to 85 | -35.72 percent change | Standard Deviation 293.47 |
Secondary
Percent Change in Synovial Volume From Days 1-29
Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 29. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent.
Time frame: Day 1 to Day 29
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Volume From Days 1-29 | -4.15 Percent change | Standard Deviation 46.54 |
Secondary
Percent Change in Synovial Volume From Days 1-57
Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 57. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent.
Time frame: Day 1 to Day 57
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Volume From Days 1-57 | -6.52 Percent change | Standard Deviation 31.47 |
Secondary
Percent Change in Synovial Volume From Days 1-85
Percent change in the synovial volume for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the wrist from Day 1 to Day 85. Synovial volume was evaluated by image subtraction from the T1-weighted images pre-and post-administration of the contrast agent.
Time frame: Day 1 to Day 85
Population: Full Analysis Set, composed of all participants who had a baseline and at least one post-baseline measurement. Only participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etanercept | Percent Change in Synovial Volume From Days 1-85 | 7.75 Percent change | Standard Deviation 55.33 |