Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial

Abstract

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.

Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.

Design, setting, and participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.

Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa.

Main outcomes and measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.

Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.

Conclusions and relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.

Trial registration: ClinicalTrials.gov Identifier: NCT03029208.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Singh reported receiving personal fees from GlaxoSmithKline (GSK) Consulting and income for serving as chair of the steering committee during the conduct of the study. Dr Carroll reported receiving personal fees from GSK during the conduct of the study. Dr McMurray reported receiving payment and travel and accommodation fees through Glasgow University from GSK as a co-principal investigator and steering committee member for the Harmony-Outcomes, ASCEND-D, and ASCEND-ND trials; AstraZeneca as a principal investigator of the DAPA-HF trial, co-principal investigator of the DELIVER trial, executive committee member for the DETERMINE and PRIORITIZE trials, and advisory board member for the AZD9977 trial; Bayer as a steering committee member for the FINEARTS-HF trial; Amgen as a steering committee member for the GALACTIC-HF trial; Theracos as a principal investigator for the BEST trial; DalCor Pharmaceuticals as a steering committee member for the Dal-GenE trial; Bristol Myers Squibb (BMS) as a steering committee member for the STAND-UP clinical trial; Cytokinetics as a steering committee member for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials; Novartis as an executive committee member and co-principal investigator of the ATMOSPHERE trial, co-principal investigator of the PARADIGM-HF trial, and executive/steering committee member for the PARACHUTE-HF, PARADISE-MI, and PERSPECTIVE trials as well as for participation in a company advisory board for the cardio-metabolic field; Alnylam Pharmaceuticals for participation in a company advisory board about development of ALN-AGT01; Cardurion for participation in a company advisory board; Ionis Pharmaceuticals as a consultant for the Ionis angiotensinogen program; and Boehringer Ingelheim for participation as a consultant for the Empa Pragmatic trial; he also reported receiving personal lecture fees from Corbus and KBP Biosciences as a scientific advisor and personal fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape and TheHeart.Org, ProAdWise Communications, Radcliffe Cardiology, and Servier, all outside the submitted work. Dr Perkovic reported serving on the steering committee and advisory board of GSK during the conduct of the study and receiving honoraria for Steering Committees, Advisory Board participation, and/or scientific presentations from Bayer, Janssen, AbbVie, BMS, Eli Lilly, Pfizer, Servier, AstraZeneca, Novo Nordisk, Relypsa, Baxter, Sanofi, Gilead; Novartis, Durect, Astellas, Merck, Tricida, Dimerix, Mundipharma; UpToDate; Mitsubishi Tanabe, Mundipharma, Travere, and Otsuka outside the submitted work. Dr Jha reported receiving personal fees paid to the institution from GSK during the conduct of the study and from AstraZeneca, Baxter Healthcare, Zydus Cadila, Bayer, and Boehringer Ingelheim outside the submitted work. Dr Johansen reported receiving personal fees from and serving on the trial steering committee for GSK during the conduct of the study and receiving personal fees from and serving on the advisory board for Akebia outside the submitted work. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, GSK, Medtronic, Merck, Pfizer, Portola, and Sanofi and grants from BMS, GSK, Medtronic, Pfizer, and Sanofi outside the submitted work. Dr Macdougall reported receiving personal fees from GSK during the conduct of the study and from GSK and Vifor Pharma outside the submitted work. Dr Obrador reported receiving personal fees from and serving on the steering committee for GSK during the conduct of the study; receiving personal fees from and serving on the advisory board for Roche Mexico outside the submitted work; and serving as the national leader for Mexico, Colombia, and Guatemala for the Janssen Research & Development CREDENCE trial. Dr Waikar reported receiving personal fees from GSK during the conduct of the study. Dr Wanner reported receiving personal fees from and serving on the steering committee for GSK during the conduct of the study and receiving personal fees from Akebia, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, FMC, Idorsia, Lilly, Mundipharma, MSD, Gilead, Tricida, and Vifor outside the submitted work. Dr Wheeler reported receiving personal fees from GSK during the conduct of the study and from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Mundipharma/Napp, Merck Sharp & Dohme, Tricida, Vifor, and Zydus outside the submitted work. Dr Wiecek reported serving on the steering committee for GSK during the conduct of the study, and receiving personal fees from Astellas, AstraZeneca, Bayer, GSK, Medice, Roche and Sandoz outside the submitted work. Dr Stankus reported receiving grants from GSK during the conduct of the study and from Akebia outside the submitted work. Dr Strutz reported receiving personal fees from GSK, Vifor, Bayer, Norgine, AstraZeneca, Otsuka and Astellas outside the submitted work. Ms Blackorby reported being an employee of GSK during the conduct of the study and holding stock in GSK outside the submitted work. Dr Cobitz reported being an employee of GSK during the conduct of the study and holding stock in GSK outside the submitted work. Dr Meadowcroft reported being an employee of GSK during the conduct of the study and holding stock in GSK outside the submitted work. Dr Paul reported being an employee of GSK during the conduct of the study and holding stock in GSK outside the submitted work. Dr Ranganathan reported being an employee of GSK during the conduct of the study and holding stock in GSK outside the submitted work. Dr Solomon reported receiving grants from GSK to the institution and personal fees from GSK during the conduct of the study; grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, National Institutes of Health, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos and from US2.AI to the institution; and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProthera, Moderna, American Regent, Sarepta, Lexicon, AnaCardio, Akros, and PureHealth outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. ASCEND-ID Study Design

Although investigators and patients were aware of the allocated treatment, the sponsor and steering committee remained blind to aggregate treatment assignment throughout the trial. ESA indicates erythropoiesis-stimulating agent; Hb, hemoglobin; IV, intravenous; rhEPO, recombinant human erythropoietin; SC, subcutaneous; and TSAT, transferrin saturation. aLimited use was defined as no more than 6 weeks of short-acting ESA (rhEPO or biosimilars; maximum of 20 000 U total) or long-acting ESA (darbepoetin alfa [maximum of 100 μg total] or methoxy polyethylene glycol-epoetin beta [maximum of 125 μg total]) received before or after starting dialysis. bSI conversion factor: To convert hemoglobin to grams per liter, multiply by 10.0. cSI conversion factor: To convert ferritin to micrograms per liter, multiply by 1.0.

Figure 2.. CONSORT Diagram

aPatients may have had more than 1 reason for exclusion; thus, the numbers sum to more than the total. I/E, inclusion/exclusion; ITT, intent-to-treat; and RT, randomized treatment.

Figure 3.. Line Plots for Mean Hemoglobin Levels and Mean On-Treatment Monthly IV Iron Dose

Dashed vertical lines indicate the evaluation period and whiskers, 95% CIs. BL, baseline; FU, follow-up; IV, intravenous; and SCR, screening. To convert hemoglobin to grams per liter, multiply by 10.0.