The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

Abstract

Objectives: To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone.

Methods: MTX-naive, early RA patients with ≤12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52.

Results: 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX.

Conclusions: In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients.

Trial registration number: (NCT01451203).

Keywords: Anti-TNF; Disease Activity; Early Rheumatoid Arthritis; Inflammation; Rheumatoid Arthritis.

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Figures

Figure 1

Patient disposition. *Patients who did not achieve an improvement of RA symptoms (defined as the persistence of DAS28[ESR] ≥3.2 for 4 weeks or longer) after Week 24 were eligible to withdraw from DB and move to rescue treatment with open label CZP. CZP, certolizumab pegol; DAS28, Disease Activity Score 28-joint assessment; DB, double blind; ESR, erythrocyte sedimentation rate; FAS, full analysis set; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis.

Figure 2

(A) Change from baseline in modified Total Sharp Score (mTSS CFB) at weeks 24 and 52. For calculation of p values, an ANCOVA model was used for mTSS CFB by converting measured values to rank scores and using treatment group as a factor and baseline rank score as a covariate. Values in the figure indicate mean (SD) at each time point and treatment group. (B) Cumulative probability plot of mTSS CFB at week 52. Percentages in the figure indicate non-progression (mTSS CFB ≤0.5) rates of each treatment group. P value is calculated by Fisher's exact test. The mTSS data used in (A) and (B) are all imputed using linear extrapolation (LINEAR) for FAS. The number of patients in the CZP+MTX group is 158 despite the FAS reported as 159 because one patient in the group had no mTSS data after treatment. CZP, certolizumab pegol; MTX, methotrexate; mTSS, modified total Sharp score; PBO, placebo.

Figure 3

(A) Clinical remission rates at weeks 24 and 52 by Simple Disease Activity Index (SDAI), Boolean and Disease Activity Score 28-joint assessment (DAS28) (erythrocyte sedimentation rate (ESR)) criteria analysed using full analysis set (FAS), last observation carried forward (LOCF) data set. Error bars indicate 95% confidence interval of each remission rate. P values are calculated by Fisher's exact test. (B-E) Time course of American College of Rheumatology (ACR) response rates of (B) ACR20, (C) ACR50, (D) ACR70 and (E) Health Assessment Questionnaire Disability Index (HAQ-DI) remission rates. *p