Rheumatoid Arthritis
Conditions
Keywords
RA, painful joints, swollen joints
Brief summary
The purpose of this study is to 1)to determine if it is better to treat all early RA patients with methotrexate in combination with hydroxychloroquine plus sulfasalazine or in combination with etanercept or reserve this treatment for patients who do not appropriately respond to methotrexate alone and 2) to determine which combination of methotrexate therapy is better
Detailed description
The ultimate goal of RA is to eliminate symptoms, restoring the patient to normal physical, social, emotional, and vocational function, and preserving the structure and integrity of joints. While disease modifying anti-rheumatic drugs (DMARDs) have long been the cornerstone of RA therapy, the limitations of DMARDs have become increasingly apparent and investigators continue to gain insight into the pathogenesis of this disease. Recent evidence suggests that treatment earlier in the disease process with more aggressive approaches results in superior long-term outcomes compared to less intensive treatment regimens. Specifically, there is growing interest in the possibility that early aggressive treatment with combinations of DMARDs as initial treatment in efforts to potentially reduce the proportion of patients that advance to severe disability.
Interventions
DRUGmethotrexate
varies
DRUGsulfasalazine
varies
DRUGhydroxychloroquine
varies
DRUGetanercept
varies
Sponsors
Amgen
Barr Laboratories
Pfizer
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of RA for less than or equal to 3 years * Be 18 years of age or older at the time of diagnosis
Exclusion criteria
* Pregnant or lactating women * History of chronic infection, such as hepatitis, pneumonia, or chronic skin infections * Active TB or evidence of latent TB
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR) | Change of the Mean of DAS28-ESR between weeks 48 - 102. | Outcome measured was the observed-group analysis of the DAS28-ESR between weeks 48 and 102. DAS28 is a calculated scale using a formula that includes the number of tender joints and swollen joints (28 joints maximum). The following is the calculation: DAS28 = 0.56 \* sqrt(tender28) + 0.28 \* sqrt(swollen28) + 0.70 \* ln(ESR) + 0.014 \* GH. The ESR is the rate at which red blood cells sediment in a period of one hour. The total range for the DAS28ESR goes from 0.0 to 9.2; this indicates the current activity of the rheumatoid arthritis of a subject. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores. | Year 2, Week 102 | Changes in disease progression between treatment groups will be described by the mean score at two years as assessed after adjustment for the baseline radiographic score. Radiographs were observed of hands, wrists, and feet. The range of scores available for the modified Sharp Score is 0 to 448. The erosion score per joint of the hands can range from 0 to 5. The maximal erosion score for each hand is thus 80, considering the 16 areas for erosions per hand. Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4 with a max score of 60. The erosion score per joint can range from 0 to 10, with each side of the joint independently scored from 0 to 5. The maximal erosion score per foot is thus 60. The joint space narrowing and joint (sub)luxation are combined in a single score with a range of 0 to 4. The maximal narrowing/(sub)luxation score per foot is thus 24. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in May 2004 and concluded in January 2007.
Pre-assignment details
This study had a screening period of 1-3 days, Patients were excluded for various reasons, including, laboratory exclusions, Positive TB test, and Cataract/visual defect.
Participants by arm
| Arm | Count |
|---|---|
| MTX + Active Etanercept Methotrexate (MTX) + etanercept | 244 |
| MTX+ Active SSZ +HCQ methotrexate (MTX) + sulfasalazine (SSZ)/hydroxychloroquine (HCQ) | 132 |
| MTX + Placebo Entaneracept methotrexate (MTX) or MTX + Etanercept | 255 |
| MTX + Placebo SSZ + HCQ(ST) methotrexate (MTX) or MTX + sulfasalazine (SSZ)/hydroxychloroquine (HCQ) | 124 |
| Total | 755 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 5 | 2 |
| Overall Study | Death | 1 | 1 | 2 | 0 |
| Overall Study | Lost to Follow-up | 19 | 8 | 18 | 15 |
| Overall Study | non medical reason | 6 | 2 | 10 | 3 |
| Overall Study | Physician Decision | 6 | 4 | 7 | 2 |
| Overall Study | Serious Adverse Event | 8 | 2 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 33 | 25 | 29 | 19 |
Baseline characteristics
| Characteristic | MTX+ Active SSZ +HCQ | MTX + Placebo Entaneracept | MTX + Active Etanercept | MTX + Placebo SSZ + HCQ(ST) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 132 Participants | 255 Participants | 244 Participants | 124 Participants | 755 Participants |
| Age, Continuous | 48.8 years STANDARD_DEVIATION 12.7 | 48.6 years STANDARD_DEVIATION 13 | 50.7 years STANDARD_DEVIATION 13.4 | 49.3 years STANDARD_DEVIATION 12 | 49.4 years STANDARD_DEVIATION 12.8 |
| Region of Enrollment United States | 132 participants | 255 participants | 244 participants | 124 participants | 755 participants |
| Sex: Female, Male Female | 101 Participants | 176 Participants | 181 Participants | 87 Participants | 545 Participants |
| Sex: Female, Male Male | 31 Participants | 79 Participants | 63 Participants | 37 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 184 / 244 | 99 / 132 | 180 / 255 | 89 / 124 |
| serious Total, serious adverse events | 35 / 244 | 18 / 132 | 32 / 255 | 16 / 124 |
Outcome results
Primary
Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR)
Outcome measured was the observed-group analysis of the DAS28-ESR between weeks 48 and 102. DAS28 is a calculated scale using a formula that includes the number of tender joints and swollen joints (28 joints maximum). The following is the calculation: DAS28 = 0.56 \* sqrt(tender28) + 0.28 \* sqrt(swollen28) + 0.70 \* ln(ESR) + 0.014 \* GH. The ESR is the rate at which red blood cells sediment in a period of one hour. The total range for the DAS28ESR goes from 0.0 to 9.2; this indicates the current activity of the rheumatoid arthritis of a subject. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity.
Time frame: Change of the Mean of DAS28-ESR between weeks 48 - 102.
Population: The participants that were randomized into this clinical trial and completed the study to year 2, represent the number for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MTX + Immediate Etanercept | Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR) | 3.0 Scores on a scale | Standard Deviation 1.4 |
| MTX+ Immediate SSZ +HCQ | Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR) | 2.9 Scores on a scale | Standard Deviation 1.5 |
| MTX + Step-up Etanercept | Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR) | 3.1 Scores on a scale | Standard Deviation 1.4 |
| MTX + Step-up SSZ + HCQ(ST) | Disease Activity Score Erythrocyte Sedimentation Rate(DAS28-ESR) | 2.8 Scores on a scale | Standard Deviation 1.3 |
Secondary
Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores.
Changes in disease progression between treatment groups will be described by the mean score at two years as assessed after adjustment for the baseline radiographic score. Radiographs were observed of hands, wrists, and feet. The range of scores available for the modified Sharp Score is 0 to 448. The erosion score per joint of the hands can range from 0 to 5. The maximal erosion score for each hand is thus 80, considering the 16 areas for erosions per hand. Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4 with a max score of 60. The erosion score per joint can range from 0 to 10, with each side of the joint independently scored from 0 to 5. The maximal erosion score per foot is thus 60. The joint space narrowing and joint (sub)luxation are combined in a single score with a range of 0 to 4. The maximal narrowing/(sub)luxation score per foot is thus 24.
Time frame: Year 2, Week 102
Population: The participants that were randomized into this clinical trial and completed the study to year 2, represent the number for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MTX + Immediate Etanercept | Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores. | 7.0 Scores on a scale | Standard Deviation 16.6 |
| MTX+ Immediate SSZ +HCQ | Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores. | 7.3 Scores on a scale | Standard Deviation 13.3 |
| MTX + Step-up Etanercept | Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores. | 4.8 Scores on a scale | Standard Deviation 7.2 |
| MTX + Step-up SSZ + HCQ(ST) | Radiographic Disease Progression Between Baseline and Week 102 as Assessed by Van Der Heijde Modified Sharp Scores. | 6.2 Scores on a scale | Standard Deviation 8.9 |