Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study

Abstract

Objectives: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks.

Methods: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints.

Results: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY).

Conclusions: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX.

Trial registration number: NCT01519791.

Keywords: Anti-TNF; DMARDs (biologic); Early Rheumatoid Arthritis; Methotrexate.

Conflict of interest statement

PE received consultancy and speaker's fee from Pfizer, MSD, AbbVie, UCB Pharma, Roche, Bristol-Myers Squibb, Schering-Plough, Novartis and Samsung. COBIII received consultancy fees from UCB Pharma. GRB received consultancy fees from AbbVie, MSD, Pfizer, Roche and UCB Pharma. DEF received research grants from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma; consultancy fees from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma and other fees from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen, IDEC, Janssen, Gilead, NIH, Roche/Genentech, Abbott, Actelion and UCB Pharma. XM received research grants from Pfizer, GlaxoSmithKline and Roche and consultancy fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis. DvdH received consultancy fees from AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex; research grants from AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex and is Director of Imaging at Rheumatology BV. RvV received research support from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and UCB Pharma and consultancy fees from AbbVie, Biotest, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Eli-Lilly, Merck, Pfizer, Roche, UCB Pharma and Vertex. CA is an employee of UCB Pharma. IM is an employee of UCB Pharma. OP is an employee of UCB Pharma. DT is an employee of UCB Pharma. BV is an employee of UCB Pharma. MEW received research grants from Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma and consultancy fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Eli-Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma.

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Figures

Figure 1

Patient disposition in the C-EARLY study. a‘Other’ included some mandatory withdrawals at Weeks 24 and 36. In addition, two patients in the certolizumab pegol (CZP)+methotrexate (MTX) group were randomised in error, were not dosed and were withdrawn shortly afterwards as screen failures (these two subjects were included in the RS). Patients completed Week 52 if they had a Week 52 visit. FAS, full analysis set; PBO, placebo; RAD, radiographic set; RS, randomised set; SS, safety set.

Figure 2

(A) Sustained remission (sREM), sustained low disease activity (sLDA) and American College of Rheumatology (ACR)50 response at Week 52. The results are shown for FAS; sREM was defined as DAS28(ESR)

Figure 3

Cumulative probability plot of mean change from baseline in van der Heijde modified total Sharp score (mTSS) at Week 52. RAD; linear extrapolation; p values are nominal only. CZP, certolizumab pegol; MTX, methotrexate; PBO, placebo; RAD, radiographic set.

Figure 4

(A) Proportion of patients in remission (various definitions) at Week 52. The results are shown for FAS, non-responder imputation was used for missing data and ORs are estimated by logistic regression; p values shown are nominal only. (B) The mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) by visit. FAS, last observation carried forward; nominal p values are estimated by logistic regression: *p≤0.05, †p<0.001. (C) Proportion of patients in DAS28(ESR) low disease activity by visit. FAS, NRI; nominal p values are estimated by logistic regression: *p≤0.05, †p<0.001. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CZP, certolizumab pegol; EULAR, European League Against Rheumatism; FAS, full analysis set; LS, least squares; MTX, methotrexate; OR, odds ratio; PBO, placebo; SDAI, Simplified Disease Activity Index.

Figure 5

Percentage of patients with American College of Rheumatology (ACR)20/50/70 response by visit. The results are shown for FAS and non-responder imputation was used for missing data; nominal p value between groups are estimated by logistic regression: *p≤0.05 at Weeks 2, 4 and 40 (ACR20); †p≤0.05 at Weeks 2, 4, 6, 8, 12, 20, 40 and 52 (ACR50); ‡p≤0.05 at all time points (ACR70). CZP, certolizumab pegol; FAS, full analysis set; MTX, methotrexate; PBO, placebo.