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乌帕替尼和阿巴西普治疗类风湿性关节炎的比较试验
Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis


Andrea Rubbert-Roth ... 其他 • 2020.10.15
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摘要


背景

乌帕替尼(upadacitinib)是用于治疗类风湿性关节炎的口服选择性Janus激酶抑制剂。在生物制剂DMARD(缓解疾病的抗风湿药)难治的类风湿性关节炎患者中,乌帕替尼与阿巴西普(T细胞共刺激调节剂)相比的疗效和安全性尚不明确。

 

方法

在这项为期24周的3期、双盲、对照试验中,我们以1∶1的比例将患者随机分配接受乌帕替尼口服给药(每日1次,每次15 mg)或阿巴西普静脉给药,且两组均联用稳定剂量的合成DMARD治疗。主要终点是第12周时,基于C反应蛋白水平的28关节疾病活动度综合评分(DAS28-CRP;范围,0~9.4分,评分较高表示疾病活动度较高)相对于基线的变化,我们对主要终点进行了非劣效性评估。第12周时的关键次要终点是在DAS28-CRP相对于基线的变化以及在达到临床缓解(根据DAS28-CRP<2.6分)的患者百分比方面,乌帕替尼与阿巴西普相比的优效性。

 

结果

共计303例患者接受了乌帕替尼治疗,309例患者接受了阿巴西普治疗。乌帕替尼组和阿巴西普组的基线DAS28-CRP值分别为5.70分和5.88分,第12周时的平均变化分别为-2.52分和-2.00分(差异,-0.52分;95%置信区间[CI],-0.69~-0.35;非劣效性的P<0.001;优效性的P<0.001)。在乌帕替尼组和阿巴西普组中,达到缓解的患者百分比分别为30.0%和13.3%(差异,16.8个百分点;95% CI,10.4~23.2;优效性的P<0.001)。在治疗期间,乌帕替尼组发生了1例死亡、1起非致死性卒中事件和2起静脉血栓栓塞事件,并且乌帕替尼组中肝脏转氨酶水平升高的患者人数超过阿巴西普组。

 

结论

在生物制剂DMARD难治的类风湿性关节炎患者中,在DAS28-CRP相对于基线的变化和第12周时达到缓解的患者人数方面,乌帕替尼优于阿巴西普,但乌帕替尼与较多的严重不良事件相关。我们需要开展更长时间、更大规模的试验来确定乌帕替尼治疗类风湿性关节炎患者的疗效和安全性(由艾伯维公司资助;SELECT-CHOICE在ClinicalTrials.gov注册号为NCT03086343)。





作者信息

Andrea Rubbert-Roth, M.D., Jeffrey Enejosa, M.D., Aileen L. Pangan, M.D., Boulos Haraoui, M.D., Maureen Rischmueller, M.B., B.S., Nasser Khan, M.D., Ying Zhang, Ph.D., Naomi Martin, M.D., and Ricardo M. Xavier, M.D.
From the Division of Rheumatology, Cantonal Clinic St. Gallen, St. Gallen, Switzerland (A.R.-R.); AbbVie, North Chicago, IL (J.E., A.L.P., N.K., Y.Z., N.M.); Centre Hospitalier de l’Université de Montréal, Montreal (B.H.); Queen Elizabeth Hospital and University of Adelaide, Adelaide, SA, Australia (M.R.); and Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (R.M.X.). Address reprint requests to Dr. Rubbert-Roth at the Division of Rheumatology, Cantonal Clinic St. Gallen, Rorschacher Str. 95, 9007 St. Gallen, Switzerland, or at andrea.rubbert-roth@kssg.ch.

 

参考文献

1. Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol 2018;2:23-23.

2. Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391:2503-2512.

3. Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthritis Rheumatol 2019;71:1788-1800.

4. Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet 2018;391:2513-2524.

5. Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 2019;393:2303-2311.

6. van Vollenhoven R, Takeuchi T, Pangan AL, et al. Efficacy and safety of upadacitinib monotherapy in methotrexate-naïve patients with moderately to severely active rheumatoid arthritis (SELECT-EARLY): a randomized, double-blind, active-comparator, multi-center, multi-country trial. Arthritis Rheumatol 2020 July 8 (Epub ahead of print).

7. Genovese MC, Becker J-C, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114-1123.

8. Genovese MC, Covarrubias A, Leon G, et al. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum 2011;63:2854-2864.

9. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865-876.

10. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008;67:1096-1103.

11. Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis 2009;68:1708-1714.

12. Weinblatt ME, Schiff M, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum 2013;65:28-38.

13. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis 2017;76:840-847.

14. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013;381:1541-1550.

15. Smolen JS, Burmester G-R, Combe B, 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;388:2763-2774.

16. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-2581.

17. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012;64:640-647.

18. Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J Rheumatol 2007;34:1401-1414.

19. Common Terminology Criteria for Adverse Events v4.0. Bethesda, MD: National Cancer Institute, 2009. (NIH publication no. 09-7473.)

20. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-2806.

21. Schiff MH, von Kempis J, Goldblum R, Tesser JR, Mueller RB. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann Rheum Dis 2014;73:2174-2177.

22. Fransen J, van Riel PLCM. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005;23:Suppl 39:S93-S99.

23. 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.

24. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652-662.

25. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013;369:307-318.

26. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017;17:78-78.

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