Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial

J S Smolen, P Emery, G F Ferraccioli, W Samborski, F Berenbaum, O R Davies, W Koetse, O Purcaru, B Bennett, H Burkhardt, J S Smolen, P Emery, G F Ferraccioli, W Samborski, F Berenbaum, O R Davies, W Koetse, O Purcaru, B Bennett, H Burkhardt

Abstract

Objectives: This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission.

Methods: Patients were randomised 1:1 to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (every 2 weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52.

Results: Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p<0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p≤0.01 and 14.6% vs 4.1%; p≤0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, -0.25 vs placebo, -0.03; p≤0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups.

Conclusions: Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission.

Trial registration number: NCT00674362.

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

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
(A) Study design and (B) CONSORT diagram showing patient flow.
Figure 2
Figure 2
(A) Clinical Disease Activity Index (CDAI), Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission at both Weeks 20 and 24 (intent to treat (ITT) population, non-responder imputation); (B) mean CDAI scores up to week 24 (ITT population, last observation carried forward); (C) CDAI disease state at baseline, week 12 and week 24 (ITT population, LOCF).
Figure 3
Figure 3
Improvements in (A) physical function (Health Assessment Questionnaire-Disability-Index), (B) pain (visual analogue scale) and (C) Fatigue Assessment Scale (FAS) over 24 weeks (ITT population, last observation carried forward).

References

    1. Montag K, Gingold M, Boers A, et al. Disease-modifying anti-rheumatic drug usage, prescribing patterns and disease activity in rheumatoid arthritis patients in community-based practice. Intern Med J 2011;41:450–5.
    1. Conaghan PG, Hensor EM, Keenan AM, et al. Persistently moderate DAS-28 is not benign: loss of function occurs in early RA despite step-up DMARD therapy. Rheumatology (Oxford) 2010;49:1894–9.
    1. Kiely P, Walsh D, Williams R, et al. Outcome in rheumatoid arthritis patients with continued conventional therapy for moderate disease activity—the early RA network (ERAN). Rheumatology (Oxford) 2011;50:926–31.
    1. Mierau M, Schoels M, Gonda G, et al. Assessing remission in clinical practice. Rheumatology (Oxford) 2007;46:975–9.
    1. Macedo A, Oakley S, Gullick N, et al. An examination of work instability, functional impairment, and disease activity in employed patients with rheumatoid arthritis. J Rheumatol 2009;36:225–30.
    1. Puolakka K, Kautiainen H, Mottonen T, et al. Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum 2005;52:36–41.
    1. Roy S, Forster F, Hayes OA, et al. Do Patients with Moderate Rheumatoid Arthritis Experience As Much Disability and Benefit from Anti-TNF Treatment As Much As Patients with Severe Rheumatoid Arthritis?. Ann Rheum Dis 2012;69(Suppl 3):679.
    1. Smolen JS, Han C, van der Heijde DM, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis 2009;68:823–7.
    1. Aletaha D, Funovits J, Smolen JS. The importance of reporting disease activity states in rheumatoid arthritis clinical trials. Arthritis Rheum 2008;58:2622–31.
    1. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69:631–7.
    1. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492–509.
    1. Hyrich KL, Deighton C, Watson KD, et al. Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity. Rheumatology (Oxford) 2009;48:1323–7.
    1. Keystone E, Freundlich B, Schiff M, et al. Patients with moderate rheumatoid arthritis (RA) achieve better disease activity states with etanercept treatment than patients with severe RA. J Rheumatol 2009;36:522–31.
    1. Smolen JS, Nash P, Durez P, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 2013;381:918–29.
    1. Keystone E, Heijde D, Mason D, Jr., et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319–29.
    1. Fleischmann R, Vencovsky J, van Vollenhoven RF, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 2009;68:805–11.
    1. Weinblatt ME, Fleischmann R, Huizinga TW, et al. Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. Rheumatology (Oxford) 2012;51:2204–14.
    1. Kavanaugh A, Smolen JS, Emery P, et al. Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis. Arthritis Rheum 2009;61:1592–600.
    1. Strand V, Mease P, Burmester GR, et al. Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial. Arthritis Res Ther 2009;11:R170.
    1. Hazes JM, Taylor P, Strand V, et al. Physical function improvements and relief from fatigue and pain are associated with increased productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol. Rheumatology (Oxford) 2010;49:1900–10.
    1. Strand V, Smolen JS, van Vollenhoven RF, et al. Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial. Ann Rheum Dis 2011;70:996–1002.
    1. Smolen J, Landewe RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009;68:797–804.
    1. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.
    1. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011;70:404–13.
    1. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 2005;7:R796–806.
    1. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23:S100–8.
    1. Smolen JS, Aletaha D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum 2011;63:43–52.
    1. Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis 2012;71:1692–7.
    1. Charles P, Elliott MJ, Davis D, et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol 1999;163:1521–8.
    1. Ziegler S, Huscher D, Karberg K, et al. Trends in treatment and outcomes of rheumatoid arthritis in Germany 1997–2007: results from the National Database of the German Collaborative Arthritis Centres. Ann Rheum Dis 2010;69:1803–8.
    1. Sokka T, Pincus T. Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. J Rheumatol 2003;30:1138–46.
    1. Augustsson J, Neovius M, Cullinane-Carli C, et al. Patients with rheumatoid arthritis treated with tumour necrosis factor antagonists increase their participation in the workforce: potential for significant long-term indirect cost gains (data from a population-based registry). Ann Rheum Dis 2010;69:126–31.
    1. Radner H, Aletaha D, Smolen JS. Work Productivity, Quality of Life, and Health States of Different Disease Activity States in Patients with Rheumatoid Arthritis (RA). Ann Rheum Dis 2009 2009;68(Suppl 3):396.
    1. Anderson JJ, Wells G, Verhoeven AC, et al. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000;43:22–9.
    1. Yazici Y, Moniz Reed D, Klem C, et al. Greater remission rates in patients with early versus long-standing disease in biologic-naive rheumatoid arthritis patients treated with abatacept: a post hoc analysis of randomized clinical trial data. Clin Exp Rheumatol 2011;29:494–9.
    1. Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 2010;69:1286–91.
    1. Brocq O, Millasseau E, Albert C, et al. Effect of discontinuing TNFalpha antagonist therapy in patients with remission of rheumatoid arthritis. Joint Bone Spine 2009;76:350–5.
    1. Saleem B, Keen H, Goeb V, et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped?. Ann Rheum Dis 2010;69:1636–42.
    1. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 2013. Epub ahead of print
    1. ten Wolde S, Hermans J, Breedveld FC, et al. Effect of resumption of second line drugs in patients with rheumatoid arthritis that flared up after treatment discontinuation. Ann Rheum Dis 1997;56:235–9.
    1. Studenic P, Smolen JS, Aletaha D. Near misses of ACR/EULAR criteria for remission: effects of patient global assessment in Boolean and index-based definitions. Ann Rheum Dis 2012;71:1702–5.

Source: PubMed

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