Brief report: enhancement of patient recruitment in rheumatoid arthritis clinical trials using a multi-biomarker disease activity score as an inclusion criterion

Ronald F van Vollenhoven, Rebecca Bolce, Karen Hambardzumyan, Saedis Saevarsdottir, Kristina Forslind, Ingemar F Petersson, Eric H Sasso, C C Hwang, Oscar G Segurado, Pierre Geborek, Ronald F van Vollenhoven, Rebecca Bolce, Karen Hambardzumyan, Saedis Saevarsdottir, Kristina Forslind, Ingemar F Petersson, Eric H Sasso, C C Hwang, Oscar G Segurado, Pierre Geborek

Abstract

Objective: Rheumatoid arthritis (RA) clinical trials often exclude patients who have low C-reactive protein (CRP) levels, which slows enrollment into the trial. The purpose of this study was to determine whether high Multi-Biomarker Disease Activity (MBDA) scores (>44) in RA patients with low CRP levels (≤10 mg/liter) could be used as a complement to CRP levels >10 mg/liter to enhance patient recruitment without affecting clinical trial outcomes.

Methods: We evaluated patients from the Swedish Pharmacotherapy (SWEFOT) trial, which did not include any selection criteria for CRP levels. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy in MTX-naive RA patients (n = 220) and after 3-10 months of add-on therapy in patients who were incomplete responders to MTX alone (MTX-IR) (n = 127). Radiographic outcomes were assessed at 1 year in all patients. Within each cohort, the outcomes were compared between patients with a CRP level of ≤10 mg/liter and an MBDA score of >44 at the start of the respective treatment interval versus those with a CRP level of >10 mg/liter.

Results: Patients with both a CRP level of ≤10 mg/liter and an MBDA score of >44 at baseline had clinical and radiographic outcomes that were comparable to those in patients with a CRP level of >10 mg/liter at baseline. This broadened definition of the inclusion criteria identified an additional 24% of patients in the MTX-naive cohort and 47% in the MTX-IR cohort.

Conclusion: Patient recruitment into RA clinical trials may be substantially enhanced, without any decrease in clinical and radiographic outcomes, by using as an inclusion criterion "a CRP level of >10 mg/liter and/or an MBDA score of >44."

Trial registration: ClinicalTrials.gov NCT00764725.

© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1
Figure 1
Study approaches and inclusion/exclusion of patients. A, With the conventional approach, patients were classified according to their baseline C‐reactive protein (CRP) level alone (top). B, With the combined approach, patients were cross‐classified according to both their CRP level and their Multi‐Biomarker Disease Activity (MBDA) score (top). The numbers of patients from the Swedish Pharmacotherapy (SWEFOT) trial who were included/excluded according to each approach are shown for the methotrexate (MTX)–naive cohort (middle) and for the MTX–incomplete responder (MTX‐IR) cohort (bottom).

References

    1. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al, for the ATTRACT Study Group . Infliximab (chimeric anti‐tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1932–9.
    1. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al, for the PREMIER Investigators . The PREMIER study: a multicenter, randomized, double‐blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54:26–37.
    1. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud‐Mendoza C, et al. Effects of abatacept in patients with methotrexate‐resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865–76.
    1. Sokka T, Pincus T. Erythrocyte sedimentation rate, C‐reactive protein, or rheumatoid factor are normal at presentation in 35%‐45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol 2009;36:1387–90.
    1. Kay J, Morgacheva O, Messing SP, Kremer JM, Greenberg JD, Reed GW, et al. Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Res Ther 2014;16:R40.
    1. Hambardzumyan K, Bolce R, Saevarsdottir S, Cruickshank SE, Sasso EH, Chernoff D, et al. Pretreatment multi‐biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis 2015;74:1102–9.
    1. Genovese MC, Kavanaugh A, Weinblatt ME, Peterfy C, DiCarlo J, White ML, et al. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three‐month randomized, placebo‐controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. Arthritis Rheum 2011;63:337–45.
    1. Genovese MC, Greenwald MW, Alloway JA, Baldassare AR, Chase W, Newman C, et al. Efficacy and safety of baminercept in the treatment of rheumatoid arthritis (RA) results of the phase 2B study in the TNF‐IR population [abstract]. Arthritis Rheum 2009;60 Suppl:S154.
    1. Curtis JR, van der Helm‐van Mil AH, Knevel R, Huizinga TW, Haney DJ, Shen Y, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken) 2012;64:1794–803.
    1. Van der Helm‐van Mil AH, Knevel R, Cavet G, Huizinga TW, Haney DJ. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression. Rheumatology (Oxford) 2013;52:839–46.
    1. Goldman JA. Erosions are like cockroaches, when you see one there are many others you do not see. It's just one erosion! No, it is not! [letter]. Clin Exp Rheumatol 2014;32 Suppl 87:S‐5–6.
    1. Van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Coster L, Waltbrand E, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (SWEFOT trial): 1‐year results of a randomised trial. Lancet 2009;374:459–66.
    1. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty‐eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.
    1. Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, 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. Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A Simplified Disease Activity Index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003;42:244–57.
    1. Van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum 1996;39:34–40.
    1. Van der Heijde DM. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000;27:261–3.
    1. Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA, et al. Development of a multi‐biomarker disease activity test for rheumatoid arthritis. PLoS ONE 2013;8:e60635.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren