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      Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial

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          Abstract

          Introduction

          This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients.

          Methods

          In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10–12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb ≥ 10.0 g/dL and increase in Hb from baseline ≥ 1 g/dL) and mean Hb and change from baseline in Hb at weeks 18–24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events.

          Results

          Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was − 0.052 (0.142) for placebo and + 0.200 (0.160), + 0.453 (0.256), and + 0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively ( p < 0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups ( p < 0.001). Change in Hb from baseline at weeks 18–24 was − 0.17 (0.61) for placebo and + 1.10 (0.71), + 1.33 (0.82), and + 1.55 (0.88) g/dL for roxadustat TIW groups ( p < 0.001). No deaths or major adverse cardiac events occurred with roxadustat.

          Conclusion

          Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients.

          Trial registration

          ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered).

          Funding

          Astellas Pharma Inc.

          Electronic supplementary material

          The online version of this article (10.1007/s12325-019-00943-4) contains supplementary material, which is available to authorized users.

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          Most cited references 19

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          Correction of anemia with epoetin alfa in chronic kidney disease.

           Lynda Szczech,  ,  Shelly Sapp (2006)
          Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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            A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

            Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.) 2009 Massachusetts Medical Society
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              KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

               ,   (2006)
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                Author and article information

                Contributors
                akizawa@med.showa-u.ac.jp
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                5 April 2019
                5 April 2019
                2019
                : 36
                : 6
                : 1438-1454
                Affiliations
                [1 ]ISNI 0000 0000 8864 3422, GRID grid.410714.7, Showa University School of Medicine, ; Namics 301, 4-24-51 Takanawa, Minato-ku, Tokyo, Japan
                [2 ]ISNI 0000 0001 1033 6139, GRID grid.268441.d, Yokohama City University School of Data Science, ; Yokohama, Japan
                [3 ]GRID grid.418042.b, Japan/Asia Clinical Development 2, , Astellas Pharma Inc., ; Tokyo, Japan
                [4 ]ISNI 0000 0004 1793 4635, GRID grid.476166.4, Medical Science Urology and Nephrology, , Astellas Pharma Europe B.V., ; Leiden, The Netherlands
                [5 ]GRID grid.418042.b, Japan-Asia Data Science, , Astellas Pharma Inc., ; Tokyo, Japan
                Article
                943
                10.1007/s12325-019-00943-4
                6824366
                30953333
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004948, Astellas Pharma;
                Categories
                Original Research
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2019

                anemia, ckd, clinical trial, hemoglobin, nephrology, roxadustat

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