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 Pts who could not tolerate ≥15 mg/wk MTX by Wk8 were withdrawn.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.

References:

1.   
Raza Z. Ann Rheum Dis 2015;
74(5):793

2.   
Bruynesteyn K. Arthristis
Rheum 2002; 46(3): 913–20

3.    Emery P. Ann Rheum Dis 2015; 74(S2):712