Long-term safety and efficacy of certolizumab pegol in combination with methotrexate in the treatment of rheumatoid arthritis: 5-year results from the RAPID 1 trial and open-label extension

Abstract

Objectives: To examine the safety and efficacy of 5-year administration of certolizumab pegol (CZP)+methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods: Eligible patients from the Rheumatoid Arthritis Prevention of Structural Damage (RAPID)1 randomised controlled trial (RCT) were treated in open-label extension (OLE) with CZP 400 mg every other week (Q2W), reduced to 200 mg Q2W after ≥6 months, +MTX. Combined safety data from RCT and OLE are presented from initiation of CZP treatment to 12 wks post last visit in patients receiving ≥1 dose of CZP (Safety population, N=958). Efficacy data are presented to start of first site closure (wk 256 of CZP treatment: 52 wks in RCT+204 wks in OLE) for all patients randomised to receive CZP (intent-to-treat (ITT) population, N=783) and CZP patients who completed the 52 wk RCT and enrolled into OLE (wk 52 CZP completers, N=508). Disease Activity Score (DAS)28 (Erythrocyte Sedimentation Rate (ESR)), American College of Rheumatology Criteria (ACR) 20/50/70, Health Assessment Questionnaire - Disability Index (HAQ-DI), and patient retention (Kaplan-Meier analysis) were assessed.

Results: Overall event rate per 100 patient-years (ER) of adverse events (AEs) was 290.4, most frequently: urinary tract infections (ER=7.9), nasopharyngitis (ER=7.3) and upper respiratory tract infections (ER=7.3). ER of serious AEs was 20.3 (infections=5.9, malignancies=1.2). 21 patients (2.2%) experienced an AE resulting in death (incidence rate=0.6). At wk 256 of treatment, 55.3% of the CZP ITT population were estimated to remain on treatment (68.7% if solely withdrawals due to AE or lack of efficacy were considered). In wk 52 CZP completers and CZP ITT population, DAS28 (ESR) remission rates and improvements from baseline were sustained to wk 256.

Conclusions: CZP+MTX treatment provided a favourable risk-benefit profile over 5 years in patients with active RA. No new safety signals were identified.

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

Figure 1

(A) Patient disposition in the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) randomised controlled trial and open-label extension and (B) Kaplan–Meier plot of time to withdrawal^† for any reason, and due to lack of efficacy or adverse effect from start of feeder study for the certolizumab pegol (CZP) intent-to-treat (ITT) population (N=783). *Withdrew from the study at week 16 per protocol; efficacy populations (CZP ITT patients and CZP completers) are highlighted. ^†Time to withdrawal is measured from the point at which a patient is first treated with CZP.

Figure 2

Percentage of patients experiencing adverse events (AEs) and serious AEs over each 6-month period from the start of the feeder study (safety population; N=958). Note, sharp decline in patient numbers from month 60 is due to per protocol site closure in countries where certolizumab pegol became commercially available.

Figure 3

Efficacy variables for week 52 certolizumab pegol (CZP) completers (N=508) and CZP intent-to-treat population (N=783). (A) Mean Disease Activity Score (DAS)28 (Erythrocyte Sedimentation Rate, ESR); (B) American College of Rheumatology Criteria (ACR)20, ACR50 and ACR70 response rates); (C) Mean Health Assessment Questionnaire – Disability Index (HAQ-DI). Efficacy variables in patients following dose reduction from CZP 400 mg Q2W to CZP 200 mg Q2W (N=436). (D) Mean DAS28 (ESR); (E) ACR20, ACR50 and ACR70 response rates. *This analysis is presented as weeks following dose-reduction visit. (‘week 0’ is defined as the final efficacy assessment visit where a patient received CZP 400 mg dose.) Total number of patients reflects imputed population. Note, sharp decline in patient numbers from week 144 following dose reduction is due to per protocol site closure in countries where CZP became commercially available.