The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

Abstract

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3–5, hemoglobin 8.5–10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11–12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24–28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3–5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events. The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3–5, hemoglobin 8.5–10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11–12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24–28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3–5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events. Lay SummaryMany people with chronic kidney disease (CKD) suffer from anemia. Anemia occurs when there are not enough hemoglobin-containing red blood cells to carry oxygen to the body’s organs. This can cause symptoms of fatigue in patients, potentially leading to a poorer quality of life. The usual treatment for anemia requires injections of man-made versions of the hormone erythropoietin, which controls red blood cell production. Daprodustat is a new oral tablet for anemia treatment that can also increase the production of red blood cells. In the ASCEND-NHQ clinical trial, 614 patients with CKD and anemia had an equal likelihood of receiving daily daprodustat or an identical placebo pill for 28 weeks. By the end of the study, people treated with daprodustat had a larger increase in hemoglobin and improvements in fatigue compared with those who received placebo and compared with their starting hemoglobin and fatigue levels. Many people with chronic kidney disease (CKD) suffer from anemia. Anemia occurs when there are not enough hemoglobin-containing red blood cells to carry oxygen to the body’s organs. This can cause symptoms of fatigue in patients, potentially leading to a poorer quality of life. The usual treatment for anemia requires injections of man-made versions of the hormone erythropoietin, which controls red blood cell production. Daprodustat is a new oral tablet for anemia treatment that can also increase the production of red blood cells. In the ASCEND-NHQ clinical trial, 614 patients with CKD and anemia had an equal likelihood of receiving daily daprodustat or an identical placebo pill for 28 weeks. By the end of the study, people treated with daprodustat had a larger increase in hemoglobin and improvements in fatigue compared with those who received placebo and compared with their starting hemoglobin and fatigue levels. Anemia frequently develops among patients with chronic kidney disease (CKD), and its severity increases as kidney function declines. Mild anemia contributes to the symptom burden of patients with advanced CKD, particularly causing or exacerbating fatigue and dyspnea.1Gregg L.P. Jain N. Carmody T. et al.Fatigue in nondialysis chronic kidney disease: correlates and association with kidney outcomes.Am J Nephrol. 2019; 50: 37-47Crossref PubMed Scopus (23) Google Scholar,2Mathias S.D. Blum S.I. Sikirica V. et al.Symptoms and impacts in anemia of chronic kidney disease.J Patient Rep Outcomes. 2020; 4: 64Crossref PubMed Scopus (8) Google Scholar Early placebo-controlled trials of recombinant human erythropoietin (rhEPO) showed substantial anemia improvement and reductions in rates of red blood cell transfusion among transfusion-dependent patients with advanced CKD or kidney failure. Increases in hemoglobin (Hb) with rhEPO were accompanied by amelioration of fatigue, physical symptoms, and physical function, compared with placebo or the untreated comparator group in these small, randomized studies.3Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar, 4US Recombinant Human Erythropoietin Predialysis Study GroupDouble-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients.Am J Kidney Dis. 1991; 18: 50-59Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 5Revicki D.A. Brown R.E. Feeny D.H. et al.Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients.Am J Kidney Dis. 1995; 25: 548-554Abstract Full Text PDF PubMed Scopus (265) Google Scholar However, in the few sizeable, blinded studies that systematically evaluated the effects of treating anemia related to CKD with erythropoiesis-stimulating agents (ESAs) in patients with non-dialysis-dependent CKD, the benefits to health-related quality of life (HRQoL), including those relating to fatigue and physical functioning, were smaller and inconsistent.6Drüeke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1822) Google Scholar, 7Lewis E.F. Pfeffer M.A. Feng A. et al.Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.Clin J Am Soc Nephrol. 2011; 6: PubMed Scopus Google Scholar, et of anemia with alfa in chronic kidney Engl J Med. 2006; 355: PubMed Scopus Google Scholar Thus, significant benefits of treatment in patients with CKD with anemia. a of as or and tested in clinical trials of participants with anemia related to agents the of including the erythropoietin that erythropoietin production. over in that are and to a increase in erythropoietin et for a randomized trial in participants on Kidney 2019; PubMed Scopus Google Scholar anemia treatment is particularly for non-dialysis-dependent patients and those on requires to oral which to in patients with T. et to in patients with chronic kidney disease: a of Kidney PubMed Scopus Google Scholar The of oral therapy of of patients and their clinical trials that are in treating anemia related to CKD, the of on not et in patients with anemia and non-dialysis-dependent Engl J Med. PubMed Scopus Google Scholar, et for the treatment of anemia in patients not Engl J Med. PubMed Scopus Google Scholar, A. et and of for anemia in patients Engl J Med. PubMed Scopus Google Scholar, M.A. et for treating anemia in patients with CKD not on from a randomized Am Soc Nephrol. PubMed Scopus Google Scholar, et for the treatment of anemia in chronic kidney disease patients not on a randomized, double-blind, placebo-controlled study PubMed Scopus Google Scholar The Anemia in a Daprodustat in and of trial was to the effects of daprodustat on and fatigue by patients with anemia related to ASCEND-NHQ was a multicenter, randomized, double-blind, placebo-controlled study in The study of of 28 of and a at weeks. participants were randomized to daprodustat or Daprodustat or placebo was daily and to achieve and maintain 11–12 This target which is with F. et to for with erythropoiesis-stimulating a by of the to with 25: PubMed Scopus Google A. Brown et association clinical on of chronic kidney Nephrol. 18: PubMed Scopus Google Scholar was as studies that an level in the 11–12 g/dl is associated with the in F. et between hemoglobin level and quality of life in patients with chronic kidney disease receiving 2006; PubMed Scopus Google Scholar Outcomes for the primary and secondary endpoints were of the study is in Adults with CKD stages with anemia related to CKD were for Anemia was as a level of g/dl at and 8.5–10.0 g/dl on on a blood had not treated with or blood transfusion in the to and from to were to a transferrin saturation of and a ferritin level ng/ml at and of oral or a change in oral between and The period without use of or significant change in use to The of and is in the The study was by or at study and participants who the period were randomized to oral daprodustat or oral placebo on was by and were blinded to The starting of daprodustat or placebo was on the level on 1 daily the level was daily the level was g/dl). 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Brown et association clinical on of chronic kidney Nephrol. 18: PubMed Scopus Google Outcomes Anemia for Anemia in Kidney Full Text Full Text PDF Scopus Google Scholar Early rhEPO in which participants with in the of to g/dl and increases in showed improvements in in fatigue or increases in Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar, 4US Recombinant Human Erythropoietin Predialysis Study GroupDouble-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients.Am J Kidney Dis. 1991; 18: 50-59Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 5Revicki D.A. Brown R.E. Feeny D.H. et al.Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients.Am J Kidney Dis. 1995; 25: 548-554Abstract Full Text PDF PubMed Scopus (265) Google Scholar In a with CKD, and baseline level g/dl in the to with E.F. Pfeffer M.A. Feng A. et al.Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.Clin J Am Soc Nephrol. 2011; 6: PubMed Scopus Google Scholar, M.A. et trial of alfa in diabetes and chronic kidney Engl J Med. 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Pfeffer M.A. Feng A. et al.Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.Clin J Am Soc Nephrol. 2011; 6: PubMed Scopus Google Scholar The by Early Anemia with and the of and Outcomes in studies evaluated the of treatment on the of these trials are not to those of as these studies had placebo were and an level of T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1822) Google et of anemia with alfa in chronic kidney Engl J Med. 2006; 355: PubMed Scopus Google Scholar The ASCEND-NHQ are potentially that a clinically improvement in fatigue can compared with placebo, in a non-dialysis-dependent CKD with baseline level in the g/dl However, can as to change in quality of life is to daprodustat or the of an anemia treatment to and fatigue level associated with anemia of in baseline as and between the treatment the improvement in the SF-36 Vitality score with daprodustat in the that the baseline not the SF-36 Vitality score of daprodustat on level and the SF-36 Vitality score were similar by and The increase in level was greater among participants level was at the increase in level not among those who were or at the SF-36 Vitality the of effects and is studies that and with CKD SF-36 Vitality and et of life and its among patients with chronic kidney disease: a 2019; PubMed Scopus Google Scholar Daprodustat also the SF-36 Vitality score to a similar among participants level was g/dl at baseline and those level was between and g/dl, association was between level and change in SF-36 Vitality difference was in of oral or between the daprodustat and placebo the study period that the difference in Thus, participants with and a in A of ASCEND-NHQ is its study of study participants and to study treatment and is particularly when these endpoints to et of life and its among patients with chronic kidney disease: a 2019; PubMed Scopus Google Scholar However, the study also that The primary of mean change in the SF-36 Vitality score for of participants who treatment to 28 or had and the primary of mean change in level from baseline to the for of participants who had However, that not were with the primary The study not a substantial proportion of patients with of participants had a level g/dl at trial an level of 11–12 is an target for in of the as the F. et to for with erythropoiesis-stimulating a by of the to with 25: PubMed Scopus Google Scholar, A. 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