Nan Chen1, Chuanming Hao1, Bi-Cheng Liu1, Hongli Lin1, Caili Wang1, Changying Xing1, Xinling Liang1, Gengru Jiang1, Zhengrong Liu1, Xuemei Li1, Li Zuo1, Laimin Luo1, Jianqin Wang1, Ming-Hui Zhao1, Zhihong Liu1, Guang-Yan Cai1, Li Hao1, Robert Leong1, Chunrong Wang1, Cameron Liu1, Thomas Neff1, Lynda Szczech1, Kin-Hung P Yu1. 1. 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.).
Abstract
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis. METHODS: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values. RESULTS: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group. CONCLUSIONS: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis. METHODS: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values. RESULTS: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group. CONCLUSIONS: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).
Authors: Elizabeth Katherine Batchelor; Pinelopi Kapitsinou; Pablo E Pergola; Csaba P Kovesdy; Diana I Jalal Journal: J Am Soc Nephrol Date: 2020-02-10 Impact factor: 10.121
Authors: Joachim Fandrey; Johannes Schödel; Kai-Uwe Eckardt; Dörthe M Katschinski; Roland H Wenger Journal: Pflugers Arch Date: 2019-11-22 Impact factor: 3.657