Disease activity improvements with optimal discriminatory ability between treatment arms: applicability in early and established rheumatoid arthritis clinical trials

Josef Smolen, Roy Fleischmann, Daniel Aletaha, Yihan Li, Yijie Zhou, Iain Sainsbury, Ivan Lagunes Galindo, Josef Smolen, Roy Fleischmann, Daniel Aletaha, Yihan Li, Yijie Zhou, Iain Sainsbury, Ivan Lagunes Galindo

Abstract

Background: The ACR20 has been validated as the best discriminator of efficacy in placebo-controlled trials, but not in head-to-head trials comparing effective therapies in patients with rheumatoid arthritis (RA). We assessed the most discriminatory ACR response and most discriminatory percent improvement in disease activity measures for Simplified Disease Activity index (SDAI), Clinical Disease Activity index (CDAI), and 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) using different patient populations and trial designs.

Methods: Data from two placebo-controlled studies in established RA and two head-to-head studies in early RA were analyzed. The numeric ACR response for each treatment and P value for the difference between treatments were calculated at multiple time points to determine the ACR response associated with the lowest P value. Similarly, values for percent improvement from baseline in SDAI, CDAI, and DAS28(CRP) with the most discrimination between treatments were examined.

Results: In the head-to-head early RA trials, the minimum P value and greatest treatment difference between the active comparator arms at 6 months was achieved at higher ACR rates and greater percent improvements in other disease activity measures. In established RA, lower responses (minimum P value and maximum treatment difference) and smaller improvements in disease activity scores had better discriminatory ability at 6 months.

Conclusions: The most discriminatory ACR response rate and percent improvement in disease activity measures were higher in head-to-head active comparator trials in early RA versus placebo-controlled trials in established RA. This difference should be considered in future clinical trial designs.

Trial registration: NCT00195663, NCT00420927, NCT00195702.

Keywords: Biologicals; Clinical trial; Disease activity; Rheumatoid arthritis.

Conflict of interest statement

JS received grants and consulting fees from AbbVie Inc., AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer, Roche and consulting fees from Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO Pharma, Novartis-Sandoz, Samsung, Sanofi, and UCB. RF received research grants and consulting fees from AbbVie. DA received grants and consulting fees from AbbVie, Janssen, Pfizer, and Roche and consulting fees from Amgen, Celgene, Eli Lilly, Merck, Novartis, Sandoz, Sanofi/Genzyme, and UCB. YL, IS, and IL are employees of AbbVie and may own stock/options. YZ is a former employee of AbbVie and may own AbbVie stock/options.

Figures

Fig. 1
Fig. 1
ACR responses in patients with early RA a PREMIER and b OPTIMA, or established RA c DE019 and d ARMADA at week 24/26. P value for difference between response rates for patients treated with ADA+MTX and PBO+MTX. ADA, adalimumab; ACR, American College of Rheumatology; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis
Fig. 2
Fig. 2
Percent change from baseline in CDAI in patients with early RA from a PREMIER and b OPTIMA, or established RA from c DE019 and d ARMADA at week 24/26. P value for difference between response rates for patients treated with ADA+MTX and PBO+MTX. ADA, adalimumab; CDAI, Clinical Disease Activity index; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis
Fig. 3
Fig. 3
Percent change from baseline in SDAI in patients with early RA from a PREMIER and b OPTIMA, or established RA from c DE019 and d ARMADA at week 24/26. P value for difference between response rates for patients treated with ADA+MTX and PBO+MTX. ADA, adalimumab; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis; SDAI, Simplified Disease Activity Index
Fig. 4
Fig. 4
Percent change from baseline in DAS28(CRP) in patients with early RA from a PREMIER and b OPTIMA, or established RA from c DE019 and d ARMADA at week 24/26. P value for difference between response rates for patients treated with ADA+MTX and PBO+MTX. ADA, adalimumab; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis

References

    1. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R, Jr, Paulus H, Strand V, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38(6):727–735. doi: 10.1002/art.1780380602.
    1. Felson DT, Anderson JJ, Lange ML, Wells G, LaValley MP. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum. 1998;41(9):1564–1570. doi: 10.1002/1529-0131(199809)41:9<1564::AID-ART6>;2-M.
    1. American College of Rheumatology Committee to Reevaluate Improvement C A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum. 2007;57(2):193–202. doi: 10.1002/art.22552.
    1. Felson DT, LaValley MP. The ACR20 and defining a threshold for response in rheumatic diseases: too much of a good thing. Arthritis Res Ther. 2014;16(1):101. doi: 10.1186/ar4428.
    1. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT. 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(1):26–37. doi: 10.1002/art.21519.
    1. Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, Guerette B, Kupper H, Redden L, Arora V, 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. 2014;383(9914):321–332. doi: 10.1016/S0140-6736(13)61751-1.
    1. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400–1411. doi: 10.1002/art.20217.
    1. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti–tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35–45. doi: 10.1002/art.10697.
    1. Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74(2):333–340. doi: 10.1136/annrheumdis-2014-206478.
    1. Aletaha D, Martinez-Avila J, Kvien TK, Smolen JS. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Ann Rheum Dis. 2012;71(7):1190–1196. doi: 10.1136/annrheumdis-2012-201491.
    1. Kivitz AJ, Gutierrez-Urena SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol. 2017;69(4):709–719. doi: 10.1002/art.39955.
    1. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC. Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626–1634. doi: 10.1136/annrheumdis-2013-204405.
    1. Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1) Ann Rheum Dis. 2017;76(6):998–1008. doi: 10.1136/annrheumdis-2016-210104.
    1. Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, DeMasi R, Soma K, Zhang R, Takiya L, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017;390(10093):457–68.
    1. Schiff M, Weinblatt ME, Valente R, van der Heijde D, Citera G, Elegbe A, Maldonado M, Fleischmann R. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014;73(1):86–94. doi: 10.1136/annrheumdis-2013-203843.
    1. Smolen JS, Burmester GR, Combe B, Curtis JR, Hall S, Haraoui B, van Vollenhoven R, Cioffi C, Ecoffet C, Gervitz L, et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet. 2016;388(10061):2763–2774. doi: 10.1016/S0140-6736(16)31651-8.
    1. Porter D, van Melckebeke J, Dale J, Messow CM, McConnachie A, Walker A, Munro R, McLaren J, McRorie E, Packham J, et al. Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet. 2016;388(10041):239–247. doi: 10.1016/S0140-6736(16)00380-9.
    1. Smolen JS, Aletaha D, Gruben D, Zwillich SH, Krishnaswami S, Mebus C. Brief report: remission rates with tofacitinib treatment in rheumatoid arthritis: a comparison of various remission criteria. Arthritis Rheumatol. 2017;69(4):728–734. doi: 10.1002/art.39996.
    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(1):43–52. doi: 10.1002/art.27740.

Source: PubMed

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