The first study of certolizumab pegol in combination with methotrexate in DMARD-naïve early rheumatoid arthritis patients led to sustained clinical response and inhibition of radiographic progression at 52 weeks: The C-early randomized, double-blind, controlled phase 3 study

Background: C-EARLY is a phase 3 study in DMARD-naïve patients (pts) with early active RA. Objectives: To assess efficacy and safety of certolizumab pegol (CZP)+MTX vs placebo (PBO)+MTX treatment in inducing and maintaining sustained clinical response and inhibiting radiographic damage in DMARD-naïve pts with early active RA. Methods: Eligible pts in this multicenter, double-blind, randomized study (NCT01519791) were DMARD-naïve and had early, active RA.:<1 year since diagnosis at baseline (BL) fulfilling 2010 ACR/EULAR criteria; ≥4 swollen and ≥4 tender joints; DAS28(ESR)≥3.2; CRP≥10mg/L and/or ESR≥28mm/hr, rheumatoid factor or ACPA positive. Pts were randomized 3:1 to CZP (400mg Wks 0,2,4 then 200mg every 2 wks to Wk52)+MTX or PBO+MTX. MTX was initiated at 10mg/wk and up to 25mg/wk by Wk8, maximum tolerated dose was maintained to Wk52. Primary endpoint was sustained DAS28(ESR) remission (sREM, DAS28[ESR]≤2.6 at Wk40 and Wk52) and key secondary endpoint was sustained low disease activity (sLDA) (DAS28[ESR]≤3.2 at Wk40 and Wk52). Other secondary endpoints (included in hierarchical testing) were Wk52 ACR50 response, change from BL in HAQ-DI and change from BL in van der Heijde modified total Sharp score (mTSS). Results: 660 (CZP+MTX) and 219 (PBO+MTX) pts were randomized. 655 vs 213 were included in full analysis set (FAS; pts with BL and post-BL DAS28[ESR]) and 528 vs 163 in radiographic analysis set (FAS pts with valid BL and post-BL radiographs), respectively. BL characteristics were balanced between arms. 96.5% pts had high disease activity (DAS28[ESR]>5.1), 77.8% had erosions; mean TJC and SJC 15.8 and 12.5, respectively. Mean MTX dose after Wk8 was 21.1 (CZP+MTX) and 22.3 (PBO+MTX) mg/wk. Primary (sREM) and secondary endpoints in hierarchical testing (sLDA, ACR50, HAQ-DI change from BL, mTSS change from BL) were statistically significant (Figure shows all except HAQ-DI LS mean change from BL, -1.00 vs -0.82, p<0.001). Lower Erosion Score, Joint Space Narrowing (Figure) and higher proportion of pts with mTSS non-progression (70.3% vs 49.7%) were seen with CZP+MTX vs PBO+MTX. AE incidence rates were similar for both arms. Infections were higher with CZP+MTX (71.8 [CZP+MTX] vs 52.7 [PBO+MTX]/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; 1 systemic tuberculosis); 1 with PBO+MTX (respiratory failure). No new safety signals for CZP were reported. Conclusions: This first report of efficacy and safety of CZP+MTX in DMARDnaïve early RA showed CZP+MTX resulted in more pts in sREM and sLDA; greater improvements in RA signs and symptoms including physical function; and inhibition of structural damage compared with PBO+MTX. Safety profile of CZP+MTX was similar to PBO+MTX. (Figure Presented).