Arthritis, Rheumatoid
Conditions
Keywords
rheumatoid arthritis
Brief summary
In a randomized controlled clinical trial, investigators will compare the effects on \[18F\]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) from two treatment regimens in rheumatoid arthritis (RA) patients deemed methotrexate inadequate responders (MTX-IRs). Two common RA treatments will be compared: triple therapy (sulfasalazine, methotrexate, and hydroxychloroquine) versus tumor necrosis factor (TNF) inhibitor (etanercept or adalimumab, plus background methotrexate for all subjects and hydroxychloroquine for subjects who were taking this at screening).
Detailed description
Consenting subjects will be screened for eligibility and randomized to a treatment arm. Subjects will be randomized to a treatment arm with either synthetic disease-modifying antirheumatic drugs (DMARDs) \[triple therapy: sulfasalazine, methotrexate, and hydroxychloroquine\] or biologic DMARDs \[etanercept or adalimumab, plus background methotrexate for all subjects and hydroxychloroquine for subjects who were taking this at screening\]. Once randomized, a baseline visit will be conducted with each subject. Baseline data collection includes questionnaires, disease activity score, and the first FDG-PET/CT imaging. After the baseline at week 0, subjects will visit with their rheumatologist at weeks 6, 12, 18, and 24 for safety labs and further collection of disease activity scores and questionnaires. The second FDG-PET/CT will be performed at week 24. Blood specimens will be collected at weeks 0, 6, 18, and 24 for bioassays. Subject participation will end after the week 24 visit. Patients and care providers will be unblinded. The FDG-PET/CT image readers will be blinded to treatment arm as well as timepoint of image acquisition.
Interventions
DRUGMethotrexate
Subjects entering trial will continue on MTX dose of at least 15mg MTX/week. At the discretion of the treating rheumatologist, may be switched to SQ route.
DRUGSulfasalazine
1 gm bid
DRUGHydroxychloroquine
200 mg twice daily, not to exceed 6.5mg/kg
DRUGEtanercept
50 mg SC weekly
DRUGAdalimumab
40 mg SQ every other week
Sponsors
Columbia University
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Fulfill American College of Rheumatology/European League Against Rheumatism 2010 criteria for RA * Men ≥ 45 years and women ≥ 50 years * MTX monotherapy for ≥ 8 weeks at ≥ 15mg weekly or ≥ 7.5 mg weekly with a documented intolerance to higher doses * No non-biologic DMARDs in preceding two months (other than MTX and HCQ) * Disease Activity Score-28 \> 3.2 * Able to sign informed consent
Exclusion criteria
* Use of biologic DMARD within the past 6 months or use of rituximab ever * Current use of \>10mg per day of prednisone * Use of a high-intensity statin lipid lowering drug or PCSK9 inhibitor in the past 12 months * Prior patient reported, physician diagnosed clinical cardiovascular (CV) event * Insulin-dependent or uncontrolled diabetes mellitus (DM) * Systemic lupus erythematosus (SLE) or other autoimmune and chronic inflammatory diseases (i.e. inflammatory bowel disease, sarcoidosis) * Cancer treated in the last 5 years (except basal and squamous cell) or any lymphoma or melanoma * Known pregnancy, HIV, Hepatitis B Virus, Hepatitis C Virus, active (or untreated latent) tuberculosis * Baseline: liver, renal or blood count abnormalities, Glucose-6-phosphate dehydrogenase (G6PD) deficiency * Known sulfa allergy, macular disease or hypersensitivity to treatments; known demyelinating disease; uncompensated Congestive Heart Failure (CHF) * Intra-articular injection within the 4 weeks prior to baseline FDG PET/CT * 2 or more high dose radiation scans in the past year (CT scan with contrast, angiogram, SPECT nuclear medicine scan, myocardial/cardiac perfusion scan)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Vascular Inflammation as Measured by FDG-PET/CT at 6 Months | 0, 6 months | The primary outcome was the change in the mean of the maximum of the target to background ratio (TBR) in the most diseased segment (MDS) of of the index vessel as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). The index vessel is the vessel (either aorta, left carotid, or right carotid) with the highest meanmaxTBR at baseline. Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the MDS of the Aorta | 0, 6 months | The outcome was the change in the mean of the maximum of the target to background ratio (TBR) in the most diseased segment (MDS) of the aorta as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution. |
| Change From Baseline in the Average TBR of the Aorta | 0, 6 months | The outcome was the change in the target to background ratio (TBR) of the aorta as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution. |
| Change From Baseline in the Average TBR of the Bilateral Carotids | 0, 6 months | The outcome was the change in the target to background ratio (TBR) of the average of the left and right carotids as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). The baseline values of the left and right carotids were averaged and then the follow-up values of the left and right carotids were averaged resulting in one value at each time point. Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution. |
| Change From Baseline in the Average TBR of the Index Vessel | 0, 6 months | The outcome was the change in the target to background ratio (TBR) in the index vessel as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Triple Therapy (MTX+SSZ+HCQ) Sulfasalazine (SSZ) 1 g bid and hydroxychloroquine (HCQ) 200 mg twice daily, not to exceed 6.5mg/kg HCQ (in addition to concomitant methotrexate \[MTX\]).
Methotrexate: Subjects entering trial will continue on MTX dose of at least 15mg MTX/week. At the discretion of the treating rheumatologist, may be switched to SQ route.
Sulfasalazine: 1 gm bid
Hydroxychloroquine: 200 mg twice daily, not to exceed 6.5mg/kg | 57 |
| TNF Inhibitor (Etanercept or Adalimumab) etanercept 50 mg subcutaneously weekly or adalimumab 40 mg subcutaneously every other week (in addition to concomitant methotrexate, plus hydroxychloroquine, for subjects who were taking this at screening). Biologic treatment will be assigned randomly.
Methotrexate: Subjects entering trial will continue on MTX dose of at least 15mg MTX/week. At the discretion of the treating rheumatologist, may be switched to SQ route.
Etanercept: 50 mg SC weekly
Adalimumab: 40 mg SQ every other week | 58 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Poor Adherence | 0 | 1 |
| Overall Study | Poor quality scan/scan not able to be analyzed | 13 | 9 |
| Overall Study | Scan protocol not followed | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Triple Therapy (MTX+SSZ+HCQ) | TNF Inhibitor (Etanercept or Adalimumab) | Total |
|---|---|---|---|
| Age, Continuous | 59.0 years | 58.0 years | 58.0 years |
| DAS28-CRP | 4.6 units on a scale | 4.9 units on a scale | 4.8 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 15 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 43 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 43 Participants | 39 Participants | 82 Participants |
| Sex: Female, Male Male | 14 Participants | 19 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 0 / 79 |
| other Total, other adverse events | 0 / 80 | 0 / 79 |
| serious Total, serious adverse events | 4 / 80 | 10 / 79 |
Outcome results
Primary
Change From Baseline in Vascular Inflammation as Measured by FDG-PET/CT at 6 Months
The primary outcome was the change in the mean of the maximum of the target to background ratio (TBR) in the most diseased segment (MDS) of of the index vessel as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). The index vessel is the vessel (either aorta, left carotid, or right carotid) with the highest meanmaxTBR at baseline. Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution.
Time frame: 0, 6 months
Population: Participants with a FDG-PET/CT at baseline and six months for whom the primary outcome could be assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy (MTX+SSZ+HCQ) | Change From Baseline in Vascular Inflammation as Measured by FDG-PET/CT at 6 Months | -0.19 ratio | Standard Deviation 0.51 |
| TNF Inhibitor (Etanercept or Adalimumab) | Change From Baseline in Vascular Inflammation as Measured by FDG-PET/CT at 6 Months | -0.24 ratio | Standard Deviation 0.51 |
p-value: 0.7995% CI: [-0.19, 0.15]ANCOVA
Secondary
Change From Baseline in the Average TBR of the Aorta
The outcome was the change in the target to background ratio (TBR) of the aorta as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution.
Time frame: 0, 6 months
Population: Participants with a FDG-PET/CT at baseline and six months for whom the outcome could be assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy (MTX+SSZ+HCQ) | Change From Baseline in the Average TBR of the Aorta | -0.06 Ratio | Standard Deviation 0.34 |
| TNF Inhibitor (Etanercept or Adalimumab) | Change From Baseline in the Average TBR of the Aorta | -0.02 Ratio | Standard Deviation 0.43 |
p-value: 0.0595% CI: [-0.11, 0.18]ANCOVA
Secondary
Change From Baseline in the Average TBR of the Bilateral Carotids
The outcome was the change in the target to background ratio (TBR) of the average of the left and right carotids as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). The baseline values of the left and right carotids were averaged and then the follow-up values of the left and right carotids were averaged resulting in one value at each time point. Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution.
Time frame: 0, 6 months
Population: Participants with a FDG-PET/CT at baseline and six months for whom the outcome could be assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy (MTX+SSZ+HCQ) | Change From Baseline in the Average TBR of the Bilateral Carotids | -0.10 Ratio | Standard Deviation 0.51 |
| TNF Inhibitor (Etanercept or Adalimumab) | Change From Baseline in the Average TBR of the Bilateral Carotids | -0.06 Ratio | Standard Deviation 0.48 |
p-value: 0.0595% CI: [-0.2, 0.19]ANCOVA
Secondary
Change From Baseline in the Average TBR of the Index Vessel
The outcome was the change in the target to background ratio (TBR) in the index vessel as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution.
Time frame: 0, 6 months
Population: Participants with a FDG-PET/CT at baseline and six months for whom the outcome could be assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy (MTX+SSZ+HCQ) | Change From Baseline in the Average TBR of the Index Vessel | -0.07 Ratio | Standard Deviation 0.47 |
| TNF Inhibitor (Etanercept or Adalimumab) | Change From Baseline in the Average TBR of the Index Vessel | -0.09 Ratio | Standard Deviation 0.43 |
p-value: 0.0595% CI: [-0.17, 0.16]ANCOVA
Secondary
Change From Baseline in the MDS of the Aorta
The outcome was the change in the mean of the maximum of the target to background ratio (TBR) in the most diseased segment (MDS) of the aorta as measured by FDG-PET/CT scans conducted at baseline and after 24 weeks of randomized treatment allocation (MDS meanmaxTBR). Higher values indicate greater vascular inflammation. FDG uptake measurement: PET-CT images were batch-analyzed by an investigator blinded to the patients' clinical information. FDG uptake was evaluated within the wall of the ascending aorta and bilateral carotid arteries (as maximum and mean standardized FDG uptake value \[SUVmax and SUVmean, respectively\]) approximately every 5 mm on axial images. Subsequently, the target-to-background ratio (TBR) was reported (ratio of the average arterial to blood axial slice SUVmax) to correct for the blood compartment contribution.
Time frame: 0, 6 months
Population: Participants with a FDG-PET/CT at baseline and six months for whom the outcome could be assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy (MTX+SSZ+HCQ) | Change From Baseline in the MDS of the Aorta | -0.17 Ratio | Standard Deviation 0.39 |
| TNF Inhibitor (Etanercept or Adalimumab) | Change From Baseline in the MDS of the Aorta | -0.17 Ratio | Standard Deviation 0.52 |
p-value: 0.0595% CI: [-0.14, 0.17]ANCOVA