Year 1
- 24-month, randomized, double-blind, two-period trial of 542 patients with moderately to severely active RA (from ≥3 months' to ≤2 years' duration). Mean duration of disease for these patients was 9 months
- At baseline: patients were ≥18 years of age, were MTX-naive, had a DAS 28 ≥3.2, had either an erythrocyte sedimentation rate (ESR) ≥28 mm/hr or C-reactive protein (CRP) level ≥20 mg/L, and were within ACR Functional Class I, II, or III
- Corticosteroids (≤10 mg prednisone or equivalent) and NSAIDs were allowed if the dose was stable for at least 4 weeks prior to baseline. The doses were required to be kept constant through 24 weeks unless the patient experienced an adverse event. DMARDs other than MTX and ENBREL were not allowed
Study Design1,2:
- The 2-year COMET trial was divided into two periods, each lasting 1 year
- The primary objective was to compare the effects of ENBREL + MTX to MTX on clinical disease activity and radiographic change over 1 year (Period 1) in subjects with active early RA
- Results for both 1- and 2-year analyses should be viewed in context with the populations evaluated for each time point
- During Period 1 of the trial, patients were randomized to receive once-weekly ENBREL 50 mg in combination with weekly MTX (n = 274) or MTX alone (n = 268). In both the combination and monotherapy groups, initial MTX therapy dose was 7.5 mg, which was titrated to 15 mg at Week 4 if response was inadequate, and further titrated at Week 8 if patients still responded inadequately (maximum dose was 20 mg/week)
- From Weeks 8 to 52, the mean (median) MTX therapy doses were: ENBREL + MTX = 16 mg/week (17 mg/week); MTX monotherapy = 17 mg/week (20 mg/week)
Treatment Groups1,2:
- Subjects were randomized at the baseline visit equally to 1 of 4 groups
- Group 1A: ENBREL + MTX in Periods 1 and 2
- Group 1B: ENBREL + MTX in Period 1 and ENBREL alone in Period 2
- Group 2A: MTX alone in Period 1 and ENBREL + MTX in Period 2
- Group 2B: MTX in Periods 1 and 2
- 131 (24.2%) subjects discontinued during Year 1 of the study: 79 (29.5%) in the MTX group and 52 (19%) in the ENBREL + MTX treatment group
1-Year Endpoints2:
- Clinical endpoints included: DAS 28 clinical remission at Month 12, DAS 44 clinical remission, and ACR 20/50/70
- Radiographic endpoint: change in mTSS at Month 12 (components of TSS are joint space narrowing and joint erosion scores)
Safety Analyses1,2:
- Safety was analyzed using the intent-to-treat (ITT) population (N = 542), which was defined as all enrolled subjects in the trial who received at least 1 dose of the study drug
Efficacy Analyses2:
- The primary clinical efficacy endpoint was DAS 28 clinical remission (<2.6) at Month 12
- For Period 1 analyses, the modified ITT (mITT) population included all subjects who received at least 1 dose of drug and had baseline and ≥1 postbaseline DAS 28 results (N = 265 for ENBREL + MTX, N = 263 for MTX alone)
- The primary radiographic endpoint was the change in mTSS over 12 months
- Radiographic analyses for Period 1 included only subjects with baseline and follow-up x-rays (N = 246 for ENBREL + MTX, N = 230 for MTX alone)
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Year 2
*One subject (Group 1B) discontinued at final Year 1 visit but received 1 dose of the study drug in Year 2 and was included in the Year 2 population.
Study Design1,2:
- The MTX or MTX-matching placebo dose level at the end of Period 1 was the starting dose level for MTX or MTX-matching placebo in Period 2. Subjects in Group 1B (ENBREL + MTX/ENBREL) discontinued MTX by the end of the fourth week of Period 2 (ie, by the start of Month 13 of the study). In Year 2, the mean doses of MTX (mg/week) were similar between groups: 16.19 in Group 1A, 16.26 in Group 1B (mean MTX dose reported was specific to the withdrawal period [~4 weeks]), 17.83 in Group 2A, and 18.03 in Group 2B
Treatment Groups1:
- Subjects who met inclusion criteria for Period 1 and completed Period 1 were eligible to participate in Period 2
- No re-randomization of subjects in Year 2
- 64 patients discontinued during Year 2: 7 in Group 1A, 16 in Group 2A, 18 in Group 1B, and 23 in Group 2B
2-Year Endpoints1:
- Evaluate the safety of each treatment group during Year 2
- Compare the effects of ENBREL + MTX to MTX alone on radiographic change and clinical disease activity in Period 2 in subjects who first received MTX alone for 1 year
- Compare the effects of ENBREL + MTX to ENBREL alone on radiographic change and clinical disease activity in Period 2 in subjects who first received ENBREL + MTX for 1 year
- Compare the effects of ENBREL + MTX for 2 years to MTX alone for 1 year, followed by ENBREL + MTX on radiographic change and clinical disease activity over 2 years
- Compare the effects of ENBREL + MTX on radiographic change and clinical disease activity to MTX alone over 2 years
Safety Analyses1,2:
- The ITT population (N = 411) was defined as all subjects who received at least 1 dose of study drug during Period 2
Efficacy Analyses1:
- The mITT population was defined as all subjects who received at least 1 dose of study drug and had Year 2 baseline and ≥1 post-Year 2 baseline DAS 28 results
- For other analyses, fewer subjects may have been included if they were missing data for that particular endpoint
- Data analyses performed upon completion of Year 2 included data generated by subjects during Year 1 of the COMET trial
- There were 2 baselines for Year 2 analyses: the original baseline at the beginning of Year 1 and the Year 2 baseline (Week 52)
- The radiographic ITT population received at least 1 dose of study drug and provided data at baseline, Year 1, and during Year 2
- Nonresponder imputation (NRI) population analyses included patients who received at least 1 dose of study drug and had at least 1 post-Year 1 baseline on-therapy ACR result (N = 488)
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