Certolizumab pegol in combination with methotrexate in DMARD-naive patients with active, severe, progressive rheumatoid arthritis: results from a randomized, double-blind, controlled phase 3 study

BACKGROUND/PURPOSE:

Early stages of rheumatoid arthritis (RA) may provide a therapeutic window in which biologic agents are most effective.1 C-EARLY (NCT01519791) is a phase 3 study in DMARD-naïve patients (pts) with severe, active, progressive RA assessing efficacy and safety of certolizumab pegol (CZP)+MTX vs placebo (PBO)+MTX treatment in inducing and maintaining sustained clinical response and inhibiting radiographic damage.

METHODS:

Pts in this multicenter double-blind randomized study had RA <1 year since diagnosis at baseline (BL) fulfilling the 2010 ACR/EULAR criteria; ≥4 swollen and ≥4 tender joints; DAS28(ESR)≥3.2; CRP≥10 mg/L and/or ESR≥28 mm/hr, rheumatoid factor or ACPA positive. 879 pts were randomized 3:1 to CZP (400 mg at Weeks [Wks] 0,2,4, 200 mg every 2 wks to Wk52)+MTX or PBO+MTX Q2W. MTX was initiated at 10 mg/wk and increased to 25 mg/wk by Wk8; the maximum tolerated dose per pt (optimized dose) was maintained to Wk52 in both treatment arms. Pts who could not tolerate ≥15 mg/wk MTX by Wk8 were withdrawn. Sustained DAS28(ESR) remission (sREM), defined as DAS28[ESR]≤2.6 at both Wk40 and Wk52, was the primary endpoint; sustained low disease activity (sLDA), defined as DAS28[ESR]≤3.2 at both Wk40 and Wk52, was a key secondary endpoint. Secondary efficacy variables included in the hierarchical testing were ACR50 response at Wk52, change from BL in HAQ-DI at Wk52 and change from BL at Wk52 in van der Heijde modified total Sharp score (mTSS). Pts with and without rapid radiographic progression at Wk52 (defined as change from BL mTSS>3 or >5 based on linearly extrapolated scores)2 were assessed post hoc.

RESULTS:

BL characteristics were balanced between arms (Table A). 96.5% pts had high disease activity (DAS28[ESR]>5.1), median diagnosis time was 2.6 months.3 All hierarchical endpoints were statistically significant (Table B); 28.9% of CZP+MTX vs 15% of PBO+MTX in sREM (p<0.001); 43.8% of CZP+MTX vs 28.6% of PBO+MTX in sLDA (p<0.001). Approximately 3 times more pts progressed rapidly by >3 and >5 mTSS points in PBO+MTX vs CZP+MTX (23.3% vs 7.4% and 15.3% vs 4.2%). AE incidence rates were similar for both arms. Infections were higher with CZP+MTX vs PBO+MTX (71.8 vs 52.7/100 pt-yrs), but similar for serious infections (3.3 vs 3.7/100 pt-yrs). 2 deaths were reported with CZP+MTX (1 stroke, considered not related to study drug; 1 systemic tuberculosis, considered related to study drug); 1 with PBO+MTX (respiratory failure, considered not related to study drug). No new safety signals for CZP were reported.

CONCLUSION:

CZP+MTX treatment of DMARD-naïve pts with active, severe, progressive RA resulted in a greater proportion of pts in sREM and sLDA; greater improvements in RA signs and symptoms; and inhibition of structural damage vs PBO+MTX. Safety profile of CZP+MTX was similar to PBO+MTX.