提示: 手机请竖屏浏览!

罗沙司他治疗长期透析患者的贫血
Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis


Nan Chen ... 其他 • 2019.09.12
相关阅读
• 罗沙司他治疗未接受透析的肾脏病患者的贫血 • 缺氧反应途径——向研究人员致敬

摘要


背景

罗沙司他是低氧诱导因子脯氨酰羟化酶的口服抑制剂,可刺激红细胞生成并调节铁代谢。关于与标准治疗(阿法依伯汀)相比,罗沙司他治疗透析患者贫血的疗效和安全性,我们需要更多数据。

 

方法

在中国开展的这项试验中,我们将已接受至少6周透析和红细胞生成刺激剂阿法依伯汀治疗的患者(以2∶1的比例)随机分组,分别接受每周3次、为期26周的罗沙司他或阿法依伯汀治疗。除作为挽救治疗之外,胃肠外补铁暂停。主要终点是第23~27周的平均血红蛋白水平相对于基线的平均变化。如果罗沙司他组与阿法依伯汀组之间数值差异的双侧95%置信区间下限≥-1.0 g/dL,则可以确定罗沙司他的非劣效性。我们将每组患者的剂量调整至血红蛋白水平达到10.0~12.0 g/dL。安全性是通过分析不良事件和临床实验室数值的方式评估。

 

结果

共有305例患者接受了随机分组(罗沙司他组204例,阿法依伯汀组101例),256例患者(分别为162例和94例)完成了26周治疗期。平均基线血红蛋白水平为10.4 g/dL。在第23~27周的血红蛋白水平相对于基线的平均(±SD)变化方面,罗沙司他组(0.7±1.1 g/dL)在数值上大于阿法依伯汀组(0.5±1.0 g/dL),达到统计学非劣效性(差异,0.2±1.2 g/dL;95%置信区间[CI],-0.02~0.5)。与阿法依伯汀相比,罗沙司他升高了运铁蛋白水平(差异,0.43 g/L;95% CI,0.32~0.53),维持了血清铁水平(差异,25 μg/L;95% CI,17~33),并且减小了运铁蛋白饱和度的降幅(差异,4.2个百分点;95% CI,1.5~6.9)。第27周时,罗沙司他组的总胆固醇(差异,-22 mg/dL;95% CI,-29~-16)和低密度脂蛋白胆固醇(差异,-18 mg/dL;95% CI,-23~-13)降幅均超过阿法依伯汀组。罗沙司他组的铁调素平均降幅为30.2 ng/mL(95% CI,-64.8~-13.6),而阿法依伯汀组为2.3 ng/mL(95% CI,-51.6~6.2)。罗沙司他组的高钾血症和上呼吸道感染发生率较高,而阿法依伯汀组的高血压发生率较高。

 

结论

用于治疗中国透析患者的贫血时,口服罗沙司他不劣于阿法依伯汀非消化道给药(由珐博进和珐博进[中国]医药技术开发有限公司资助;在ClinicalTrials.gov注册号为NCT02652806)。





作者信息

Nan Chen, M.D., Chuanming Hao, M.D., Ph.D., Bi-Cheng Liu, M.D., Ph.D., Hongli Lin, M.D., Ph.D., Caili Wang, B.Sc., Changying Xing, M.D., Ph.D., Xinling Liang, M.D., Ph.D., Gengru Jiang, M.D., Zhengrong Liu, M.Sc., Xuemei Li, M.D., Ph.D., Li Zuo, M.D., Ph.D., Laimin Luo, M.Sc., Jianqin Wang, Ph.D., Ming-hui Zhao, Ph.D., Zhihong Liu, M.D., Guang-Yan Cai, M.D., Ph.D., Li Hao, M.Sc., Robert Leong, M.D., Chunrong Wang, M.D., Cameron Liu, Ph.D., Thomas Neff, Lynda Szczech, M.D., M.S.C.E., and Kin-Hung P. Yu, M.D.
From the Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (N.C.), the Division of Nephrology, Huashan Hospital Fudan University (C.H.), and the Department of Nephrology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (G.J.), Shanghai, the Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine (B.-C.L.), the Department of Nephrology, First Affiliated Hospital (Jiangsu Province Hospital), Nanjing Medical University (C.X.), and the National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine (Zhihong Liu), Nanjing, First Affiliated Hospital of Dalian Medical University, Dalian (H.L.), the Department of Nephrology, First Affiliated Hospital of Baotou Medical College of Inner Mongolia University of Science and Technology, Baotou (Caili Wang), the Division of Nephrology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences (X. Liang) and the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research (Zhengrong Liu), Guangzhou, the Department of Nephrology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital (X. Li), the Department of Nephrology, Peking University People’s Hospital (L.Z.), the Renal Division, Department of Medicine, Peking University First Hospital and Institute of Nephrology, Peking University (M.Z.), and the Department of Nephrology, Chinese People’s Liberation Army General Hospital, State Key Lab of Kidney Disease, National Clinical Research Center for Kidney Disease (G.-Y.C.), Beijing, the First Affiliated Hospital of Nanchang University, Nanchang (L.L.), the Department of Nephrology, Lanzhou University Second Hospital, Lanzhou (J.W.), and the Department of Nephrology, Second Hospital of Anhui Medical University, Hefei (L.H.) — all in China; and FibroGen, San Francisco (R.L., Chunrong Wang, C.L., T.N., L.S., K.-H.P.Y.). Address reprint requests to Dr. Chen at the Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Rd., Shanghai 200025, China, or at nanchenmd@hotmail.com.

 

参考文献

1. Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS One 2014;9(1):e84943-e84943.

2. Smith RE Jr. The clinical and economic burden of anemia. Am J Manag Care 2010;16:Suppl:S59-S66.

3. Nakhoul G, Simon JF. Anemia of chronic kidney disease: treat it, but not too aggressively. Cleve Clin J Med 2016;83:613-624.

4. Hörl WH. Anaemia management and mortality risk in chronic kidney disease. Nat Rev Nephrol 2013;9:291-301.

5. KDOQI, National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 2006;47:Suppl 3:S11-S145.

6. Locatelli F, Aljama P, Bárány P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004;19:Suppl 2:1-ii47.

7. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. Am J Kidney Dis 2013;62:849-859.

8. Anaemia management in chronic kidney disease: clinical guideline: methods, evidence and recommendations. London: National Clinical Guidelines Centre, June 2015 (https://www.nice.org.uk/guidance/ng8/evidence/full-guideline-pdf-70545136. opens in new tab).

9. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584-590.

10. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010;363:1146-1155.

11. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008;74:791-798.

12. Li YB, Wang M. The challenge and measures after dialysis therapy entered in rural medical insurance of serious diseases. Chinese Health Economics 2013;10:12-14.

13. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012;23:1631-1634.

14. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21:2151-2156.

15. Semenza GL, Agani F, Booth G, et al. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int 1997;51:553-555.

16. Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle 2008;7:28-32.

17. Nangaku M, Kojima I, Tanaka T, Ohse T, Kato H, Fujita T. Novel drugs and the response to hypoxia: HIF stabilizers and prolyl hydroxylase. Recent Pat Cardiovasc Drug Discov 2006;1:129-139.

18. Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis 2016;67:912-924.

19. Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol 2016;11:982-991.

20. Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant 2015;30:1665-1673.

21. Yu KH, Chou J, Klaus S, et al. Comparable doses of FG-4592 have similar PK/PD in healthy Caucasian and Japanese subjects. Nephrol Dial Transplant 2013;28:Suppl 1:i362-i362. abstract.

22. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995;92:5510-5514.

23. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 1998;8:588-594.

24. Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol Dial Transplant 2017;32:1373-1386.

25. Center of Drug Evaluation (CFDA). Announcement on issuance of guidelines on biostatistics of drug clinical trials (no. 93, 2016). June 2016. (In Chinese) (http://www.cde.org.cn/zdyz.do?method=largePage&id=272. opens in new tab).

26. Mauri L, D’Agostino RB Sr. Challenges in the design and interpretation of noninferiority trials. N Engl J Med 2017;377:1357-1367.

27. Fishbane S, Schiller B, Locatelli F, et al. Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med 2013;368:307-319.

28. Schafer JL. Analysis of incomplete multivariate data. London: Chapman & Hall, 1997.

29. Barnard J, Rubin DB. Small-sample degrees of freedom with multiple imputation. Biometrika 1999;86:948-955.

30. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-226.

31. Gomes AC, Gomes MS. Hematopoietic niches, erythropoiesis and anemia of chronic infection. Exp Hematol 2016;44:85-91.

32. Bradbury BD, Critchlow CW, Weir MR, Stewart R, Krishnan M, Hakim RH. Impact of elevated C-reactive protein levels on erythropoiesis- stimulating agent (ESA) dose and responsiveness in hemodialysis patients. Nephrol Dial Transplant 2009;24:919-925.

33. Szczech LA, Besarab A, Saikali KG, et al. Roxadustat treatment of CKD anemia is not influenced by inflammation. Presented at the American Society of Nephrology Annual Scientific Meeting, Kidney Week 2017, New Orleans, October 31–November 5, 2017 (https://www.asn-online.org/education/kidneyweek/2017/program-abstract.aspx?controlId=2772486. opens in new tab).

34. Besarab A, Chernyavskaya E, Motylev I, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J Am Soc Nephrol 2016;27:1225-1233.

35. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996;50:1694-1699.

36. Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586-e7586.

37. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 2019;381:1001-1010.

服务条款 | 隐私政策 | 联系我们