Study Designs and References

THE PRESERVE TRIAL¹:

PRESERVE was a 2-period study of patients (N=834) with moderately active RA (DAS 28 >3.2 and ≤5.1) despite optimal doses of MTX.

• *Patients were randomized if they achieved DAS 28 ≤3.2 at Week 36 and an average DAS 28 ≤3.2 from Weeks 12 through 36.
• †In Period 2, 202 patients were randomized to receive an investigational dose of ENBREL 25 mg once weekly. ENBREL 25 mg weekly is not an FDA-approved dosage.

• Period 1 was an open-label assessment of the efficacy and safety of ENBREL + MTX over 36 weeks
• Period 2 was a double-blind, randomized, 52-week period
  • Patients entering Period 2 were required to achieve low disease activity (LDA) or remission (DAS 28 ≤3.2) at Week 36 and an average DAS 28 ≤3.2 from Week 12 through Week 36
• Use of prednisone ≤10 mg/day was allowed during the trial
• The primary endpoint was the proportion of patients achieving DAS 28 LDA at Week 88 (Period 2)
• Other key defined secondary endpoints in both periods include:
  • Proportion of patients achieving DAS 28 clinical remission
  • Proportion of patients achieving ACR 20, ACR 50, ACR 70, and ACR 90
  • Change in mTSS from baseline

THE COMET TRIAL^1-3:

• 24-month, randomized, double-blind, 2-period trial of 542 patients with moderately to severely active early 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 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/day 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
• The 2-year COMET trial was divided into 2 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 moderate to severe 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)

• 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 (19.0%) in the ENBREL + MTX treatment group

• 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 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

• 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)

• 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

• 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

• 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

The ITT population (N=411) was defined as all subjects who received at least 1 dose of study drug during Period 2

• 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 result(s)
  • 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 one 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)

THE PSORIATIC ARTHRITIS PIVOTAL TRIAL^1-4:

• Multicenter, double-blind, phase 3 trial of 205 patients with active PsA
• Mean duration of arthritic disease was about 9.1 years and mean duration of plaque psoriasis was about 19.0 years (with a qualifying target skin lesion)
• Patients were randomized to receive subcutaneous injections of ENBREL 25 mg (n=101) or placebo (n=104) administered twice weekly over the 24-week blinded treatment period
• After the 24-week period, patients continued therapy in a maintenance period of up to 6 months until all patients completed double-blind therapy. After the maintenance period, all patients received ENBREL 25 mg twice weekly in an open-label period of 48 weeks
• The data were stratified by absence or presence of concurrent MTX (either ENBREL alone [n=59] vs placebo [n=61] or ENBREL + MTX [n=42] vs placebo + MTX [n=43])
• Stable use of corticosteroids and/or NSAIDs was allowed. Of the 205 patients in the blinded study, 169 patients (81 originally receiving placebo, 88 originally receiving ENBREL) entered the open-label extension. As actual timing for radiographs may have differed from the target time points, linear extrapolation was utilized to adjust the radiographic data to the target time point
• Nonresponder imputation analysis was conducted during the double-blind portion for ACR response and skin lesion clearing, while parameters assessed during the open-label period were analyzed based on the observed population at each time point
• The primary radiographic endpoint was the annualized rate of change in TSS over 1 year of treatment
• Secondary radiographic endpoints included annualized rate of change in TSS, erosion score, and joint space narrowing score at 6, 12, and 24 months
• Radiographs of hands and wrists were taken at baseline and 6 months in the controlled portion of the trial, at initiation of open-label treatment, at 1 year and 2 years from original baseline, and at early termination from the study during either part of the study
• All patients who received at least 1 dose of study drug and who had at least 1 radiograph were to be included in the radiographic analysis. Scores were adjusted to a 6- or 12-month basis using linear interpolation/extrapolation of the observed change
• The mean duration of ENBREL exposure during the 12-month radiographic period was 331.6 days in the ENBREL group and 27.6 days in the placebo group

The Early RA Trial and Open-Label Extension Trial^1-5:

• Multicenter, double-blind, double-dummy, Phase 3 trial
• 632 MTX-naive patients with early moderately to severely active RA (≤3 years' duration) were randomized to receive twice-weekly ENBREL 25 mg (n=207), twice-weekly ENBREL 10 mg (n=208), or MTX (n=217). The mean duration of disease for these patients was 11 to 12 months
• This trial became open-label and unblinded after all patients had completed 1 year of evaluation. Patients continued through 1 year of follow-up on the treatment to which they had been randomized. At the end of Year 2, patients switched to or continued twice-weekly ENBREL 25 mg subcutaneously
• Subjects could re-enroll in the continuing open-label portion of the study upon meeting specific predefined re-enrollment inclusion criteria