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

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: 845-855Crossref PubMed Scopus (53) Google Scholar, 8Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2338) Google Scholar Thus, significant uncertainty remains about HRQoL benefits of ESA treatment in non-dialysis patients with CKD with mild anemia. Recently, a novel class of medications, known as hypoxia inducible factor (HIF) stabilizers or prolyl hydroxylase inhibitors, has been developed and tested in large clinical trials of participants with anemia related to CKD. These agents inhibit the degradation of HIF, activating various genes, including the erythropoietin gene that stimulates endogenous erythropoietin production. HIF–prolyl hydroxylase inhibitors have several potential advantages over traditional ESAs in that they are administered orally and may lead to a stable increase in plasma erythropoietin concentration.9Meadowcroft A.M. Cizman B. Holdstock L. et al.Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis.Clin Kidney J. 2019; 12: 139-148Crossref PubMed Scopus (80) Google Scholar Oral anemia treatment is particularly convenient for non-dialysis-dependent patients and those on home dialysis, but it requires adherence to taking oral medication, which has been shown to be suboptimal in patients with CKD.10Mechta Nielsen T. Frøjk Juhl M. Feldt-Rasmussen B. et al.Adherence to medication in patients with chronic kidney disease: a systematic review of qualitative research.Clin Kidney J. 2018; 11: 513-527Crossref PubMed Scopus (46) Google Scholar The choice of injectable versus oral therapy should thus be part of shared decision-making of patients and their physicians. Multiple clinical trials have demonstrated that HIF–prolyl hydroxylase inhibitors are efficacious in treating anemia related to CKD, but the effect of HIF-prolyl hydroxylase inhibitors on HRQoL has not been widely evaluated.11Chertow G.M. Pergola P.E. Farag Y.M.K. et al.Vadadustat in patients with anemia and non-dialysis-dependent CKD.N Engl J Med. 2021; 384: 1589-1600Crossref PubMed Scopus (100) Google Scholar, 12Singh A.K. Carroll K. McMurray J.J.V. et al.Daprodustat for the treatment of anemia in patients not undergoing dialysis.N Engl J Med. 2021; 385: 2313-2324Crossref PubMed Scopus (71) Google Scholar, 13Eckardt K.U. Agarwal R. Aswad A. et al.Safety and efficacy of vadadustat for anemia in patients undergoing dialysis.N Engl J Med. 2021; 384: 1601-1612Crossref PubMed Scopus (77) Google Scholar, 14Fishbane S. El-Shahawy M.A. Pecoits-Filho R. et al.Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study.J Am Soc Nephrol. 2021; 32: 737-755Crossref PubMed Scopus (79) Google Scholar, 15Shutov E. Sułowicz W. Esposito C. et al.Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, double-blind, placebo-controlled study (ALPS).Nephrol Dial Transplant. 2021; 36: 1629-1639Crossref PubMed Scopus (55) Google Scholar The Anemia Studies in CKD: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat in Non-Dialysis (ND) Participants Evaluating Hemoglobin and Quality of Life (ASCEND-NHQ) trial was designed to investigate the effects of daprodustat on Hb and fatigue experienced by patients with anemia related to CKD. ASCEND-NHQ was a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03409107) conducted in 142 centers across 14 countries. The study consisted of 4 weeks of screening, 28 weeks of treatment, and a follow-up visit at 4–6 weeks. Following screening, participants were randomized 1:1 to daprodustat or placebo. Daprodustat or placebo was dosed daily and titrated to achieve and maintain Hb 11–12 g/dl. This target range, which is consistent with European guidelines,16Locatelli F. Aljama P. Canaud B. et al.Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study.Nephrol Dial Transplant. 2010; 25: 2846-2850Crossref PubMed Scopus (132) Google Scholar,17Mikhail A. Brown C. Williams J.A. et al.Renal association clinical practice guideline on anaemia of chronic kidney disease.BMC Nephrol. 2017; 18: 345Crossref PubMed Scopus (137) Google Scholar was selected, as prior studies have shown that achieving an Hb level in the 11–12 g/dl range is associated with the greatest incremental gain in HRQoL.18Lefebvre P. Vekeman F. Sarokhan B. et al.Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa.Curr Med Res Opin. 2006; 22: 1929-1937Crossref PubMed Scopus (48) Google Scholar Outcomes for the primary and principal secondary endpoints were assessed during weeks 24–28. An overview of the study design is shown in Figure 1. Adults with CKD stages 3–5 with anemia related to CKD were eligible for inclusion. Anemia was defined as a Hb level of 8.5–10.5 g/dl at screening and 8.5–10.0 g/dl on day 1, based on a point-of-care system using venous blood (HemoCue). Participants had not been treated with ESAs, i.v. iron, or blood transfusion in the 8 weeks prior to screening, and from screening to day 1. They were required to have a transferrin saturation of ≥15% and a ferritin level ≥50 ng/ml at screening and either no receipt of oral iron or a <50% change in oral iron dose between screening and day 1. The screening period thus ensured stable Hb levels without use of ESAs or significant change in iron use prior to randomization. The complete list of inclusion and exclusion criteria is provided in the Supplementary Methods. The study was approved by institutional review boards or ethics committees at all study sites, and all participants provided written informed consent. Participants who successfully completed the screening period were randomized 1:1 to oral daprodustat or oral placebo on day 1. Randomization was stratified by region and performed centrally using interactive response technology. Participants were blinded to HemoCue Hb values. The starting dose of daprodustat or placebo was based on the HemoCue Hb level on day 1 (4 mg daily if the Hb level was 8.5– <9.0 g/dl; 2 mg daily if the Hb level was 9.0–10.0 g/dl). The dose was titrated as needed at week 2 and week 4, and every 4 weeks thereafter until week 24, to achieve and maintain an Hb level of 11–12 g/dl. Dose adjustments were made by the interactive response technology system based on the HemoCue Hb level. The dosing algorithm is described in Supplementary Table S1. Participants were allowed to take oral iron, but i.v. iron was used only among participants intolerant of oral iron or for rescue. ESAs, i.v. iron, and blood transfusion were considered rescue therapies. Details of the rescue algorithm are provided in Supplementary Table S2. Participants continued study treatment until the end of the 28-week treatment period, unless they developed a protocol-defined criterion for stopping study treatment, as detailed in the Supplementary Methods. Most laboratory data, including hematology, serum creatinine concentration, and iron panels, were collected at baseline, and at weeks 4, 16, and 28. HemoCue Hb level and central laboratory Hb level were measured at every visit from screening at week -4 to week 28. Sites used the HemoCue Hb level to determine study eligibility and dose titration at study visits, whereas central laboratory Hb levels were used to ascertain study endpoints. The Medical Outcomes Study 36-item Short Form Survey, version 2 (SF-36) and other HRQoL questionnaires were administered prior to other study procedures at the baseline and week 8, 12, and 28 study visits. The SF-36 includes 8 domains including the “vitality” domain (Vitality), which measures fatigue by assessing if an individual feels full of life, has a lot of energy, feels worn out, or feels tired. The SF-36 had a 1-week recall period. The primary endpoint was the adjusted mean change in Hb level from baseline to the evaluation period (EP; weeks 24–28). The first principal secondary endpoint was the proportion of participants with a ≥1 g/dl increase in Hb level from baseline to the EP. The second principal secondary endpoint was the change in the SF-36 Vitality score (0–100) from baseline to week 28. The primary and principal secondary endpoints were evaluated for significance in a hierarchical manner. The rest of the secondary endpoints were not adjusted for multiplicity, and nominal P values are reported. Other secondary endpoints related to Hb included the proportion of participants with a mean Hb level of 11–12 g/dl, and the percentage of time with Hb in the target range during the EP, as well as the percentage needing rescue therapy and the time to needing rescue. An additional secondary fatigue endpoint was the proportion of participants with a ≥6-point increase in the SF-36 Vitality score between baseline and week 28. Changes in blood pressure were evaluated as secondary endpoints, and changes in antihypertensive medications were evaluated as exploratory endpoints. Time to first blood transfusion, time to first rhEPO, iron usage during the study, changes in iron parameters, and mean changes in other domains of the SF-36 were all exploratory endpoints. Safety endpoints included the frequency of adverse events (AEs), potential adverse events of special interest, and serious adverse events, and although the study was not powered to detect this endpoint, the first occurrence of an adjudicated major adverse cardiovascular event (MACE), defined as a composite of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke. The MACE follow-up period began at randomization and ended at study completion or withdrawal, with the exception of death, which was included in the analysis even if it was reported after this time. Primary analyses were based on the intent-to-treat population, defined as all randomized participants regardless of whether they took the study drug, with groups based on randomized treatment assignment. For the primary and principal secondary endpoints, we used hierarchical testing with a 1-sided type 1 error of 0.025. Analyses of primary and secondary Hb outcomes included on- and off-treatment Hb values as well as imputed Hb values derived from multiple imputation under a missing-not-at-random assumption. The SF-36 Vitality score outcomes were also based on the intent-to-treat population, but only on-treatment observed scores, along with imputed values, were used for participants that were off-treatment or had missing values. Imputed values were derived from multiple imputation under a missing-at-random assumption. For all endpoints, superiority required a 1-sided P < 0.025. See the Supplementary Methods and Supplementary Table S3 for further details on imputation methodology and statistical analysis. We performed prespecified subgroup analyses by age, gender, race, ethnicity, weight, baseline Hb, iron status, comorbidities including diabetes and heart failure, and high-sensitivity C-reactive protein category. Additional supportive analyses for the primary and principal secondary Hb endpoints were performed using evaluable Hb (defined as on-treatment values that were not taken within 8 weeks following a blood transfusion or ESA treatment) without imputation. Supportive analyses for the change in SF-36 Vitality score included one analysis that included only on-treatment scores without imputation, and another that included on- and off-treatment scores without imputation. For safety endpoints, groups were defined based on actual treatment received (safety population), except for MACE endpoints, which were assessed using the intent-to-treat population. Power calculations were based on the change in the SF-36 Vitality score. We estimated that 600 participants would need to be randomized to have 540 participants with evaluable SF-36 Vitality score data, providing 79% power to detect a 5-point difference in mean change between groups on the SF-36 Vitality score, assuming a within-group SD of 21 points, and a 1-sided alpha level of 0.025.19Bjorner J.B. Wallenstein G.V. Martin M.C. et al.Interpreting score differences in the SF-36 vitality scale: using clinical conditions and functional outcomes to define the minimally important difference.Curr Med Res Opin. 2007; 23: 731-739Crossref PubMed Scopus (140) Google Scholar The primary endpoint had >99% power to detect a 1.00-g/dl difference between groups for the change in Hb level from baseline to the EP, assuming a between-participant SD of 1.5 g/dl and a 1-sided alpha of 0.025. A total of 1336 participants were assessed for eligibility; 722 (54%) failed screening because they did not meet eligibility criteria (n = 655) or because they were excluded or dropped out between screening and randomization (n = 67). The remaining 614 participants, recruited between March 5, 2018 and January 29, 2020, were randomized 1:1, with 307 participants assigned to each group (Figure 2). Of the 614 randomized participants, 98% (300 of 307) in the daprodustat group and 94% (290 of 307) in the placebo group completed the study. A total of 83% of participants (254 of 307) in the daprodustat group and 69% (211 of 307) in the placebo group completed the 28-week treatment period without permanently stopping the study drug. A protocol-defined stopping criterion was the most frequent reason for treatment discontinuation in the placebo group, and placebo participants more frequently discontinued study treatment due to needing rescue. Baseline demographic and clinical characteristics of study participants are shown in Table 1. The daprodustat and placebo groups were largely similar across baseline characteristics, although some numerical differences occurred, such as mean age 1-year older, higher mean high-sensitivity C-reactive protein levels, and a greater proportion of participants with an Hb level <9.0 g/dl in the placebo group.Table 1Baseline demographic and clinical characteristicsCharacteristicDaprodustat n = 307Placebo n = 307Age, yr66.0 (56.0–75.0)67.0 (59.0–77.0)Age category, yr <65135 (44)121 (39) 65–<7582 (27)96 (31) ≥7590 (29)90 (29)Gender Female176 (57)178 (58) Male131 (43)129 (42)Ethnicity Hispanic or Latino104 (34)103 (34) Not Hispanic or Latino203 (66)204 (66)Race American Indian or Alaska Native34 (11)34 (11) Asian30 (10)28 (9) Black or African American44 (14)47 (15) Native Hawaiian or other Pacific Islander01 (<1) White197 (64)195 (64) Mixed race2 (<1)2 (<1)Region Asia Pacific19 (6)20 (7) Eastern Europe60 (20)58 (19) Western Europe/Canada/Australia57 (19)58 (19) Latin America85 (28)85 (28) US86 (28)86 (28)Weight, kg <75157 (51)150 (49) ≥75150 (49)157 (51)History Stroke28 (9)19 (6) MI27 (9)29 (9) Diabetes187 (61)188 (61) Heart failure54 (18)52 (17) Thromboembolic events16 (5)18 (6)Smoking history Never smoked199 (65)201 (65) Current smoker16 (5)21 (7) Former smoker92 (30)84 (27) Missing01 (<1)Baseline Hb, g/dl9.80 (9.30–10.10)9.70 (9.20–10.10)Baseline Hb, g/dl <928 (9)46 (15) ≥9 and <10168 (55)151 (49) ≥10 and ≤11106 (35)99 (32) >115 (2)11 (4)CKD stage: eGFR in ml/min per 1.73 m2 Stage 2: ≥603 (<1)2 (<1) Stage 3: 30 to <6092 (30)87 (28) Stage 4: 15 to <30139 (45)137 (45) Stage 5: <1573 (24)81 (26)Iron repletion status TSAT ≥15% and ferritin ≥50 ng/ml281 (92)283 (92) TSAT ≥20% and ferritin ≥100 ng/ml194 (63)203 (66)hsCRP, mg/l2.30 (0.90–6.20)aData from n = 302.2.80 (1.10–6.75)bData from n = 300.Blood pressure, mm Hg Systolic136.0 (125.0–147.0)134.0 (125.0–146.0) Diastolic74.0 (68.0–81.0)75.0 (68.0–81.0) Mean arterial pressure95.3 (87.0–103.3)94.7 (86.7–101.7)ACEI/ARB use No233 (76)228 (74) Yes74 (24)79 (26)ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; hsCRP, high-sensitivity C-reactive protein; IQR, interquartile range; MI, myocardial infarction; TSAT, transferrin saturation.Values are n (%), or median (IQR).a Data from n = 302.b Data from n = 300. Open table in a new tab ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; hsCRP, high-sensitivity C-reactive protein; IQR, interquartile range; MI, myocardial infarction; TSAT, transferrin saturation. Values are n (%), or median (IQR). The median central laboratory Hb level overall was 9.70 g/dl, with generally higher values than those in the HemoCue Hb results; therefore, 174 participants (28%) had a baseline central laboratory Hb level >10.0 g/dl even though they met eligibility criteria on the basis of a HemoCue Hb level in the range 8.5–10.0 g/dl on day 1. Iron preparations (oral or i.v.) were used in 147 participants (48%) in the placebo group and 131 participants (43%) in the daprodustat group prior to enrollment in the study. The primary endpoint, adjusted mean change in Hb level from baseline to the EP, was greater in the daprodustat group (1.58 g/dl) than in the placebo group (0.19 g/dl). The adjusted mean treatment difference (AMD) between the daprodustat and placebo groups was 1.40 g/dl (95% confidence interval [CI]: 1.23, 1.56; 1-sided P < 0.0001). Separation of mean Hb level between daprodustat and placebo was observed within 4 weeks of initiating treatment and continued through week 28 (Figure 3). Mean Hb values in the daprodustat group were in the Hb target range (11–12 g/dl) during the EP. In the primary analysis, imputed Hb values were used for 16% of participants in the daprodustat group (4% had 1 missing Hb value, and 12% had 2 missing Hb values during the EP) and 22% of participants in the placebo group (9% had one missing Hb value, and 13% had 2 missing Hb values during the EP). See Supplementary Table S4 for the reasons Hb values were missing. Evaluable Hb level by visit is shown in Supplementary Figure S1. The AMD using evaluable Hb without imputation was 1.47 g/dl (95% CI: 1.32, 1.63; 1-sided P < 0.0001). Overall, the results of subgroup analyses were consistent with the primary analysis with little or no heterogeneity among subgroups (Figure 4), except for baseline Hb, for which the mean treatment difference was greater among participants with a lower baseline Hb level (Supplementary Table S5).Figure 4Forest plot of adjusted mean difference of postrandomization hemoglobin (Hb) level change from baseline to the evaluation period across subgroups. Observed on- and off-treatment and imputed Hb values. BMI, body mass index; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; hsCRP, high-sensitivity C-reactive protein; TSAT, transferrin saturation.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A significantly larger proportion of participants in the daprodustat group (77%) compared with the placebo group (18%) had an Hb level increase of ≥1 g/dl from baseline to the EP. The difference in response rate (daprodustat–placebo) was 56% (95% CI: 49%, 63%; 1-sided P < 0.0001). In a supportive analysis that used evaluable Hb without imputation, the difference in response rate was 65% (95% CI: 58%, 72%; 1-sided P < 0.0001). The results of subgroup analyses were consistent with the primary analysis except for the extremes of baseline Hb level (<8.5 g/dl, >11 g/dl), for which the number of participants was too low to calculate a response rate (Supplementary Figure S2). A smaller proportion of participants in the daprodustat group met rescue criteria (n = 3; <1%) compared with the placebo group (n = 32; 10%). Four participants in the daprodustat group received a blood transfusion while on treatment, compared with 15 in the placebo group, and 9 participants in the daprodustat group received rhEPO while on treatment compared with 22 in the placebo group. Secondary efficacy endpoints are presented in Table 2. Serum iron and total iron binding–capacity levels increased over the course of treatment in the daprodustat group, whereas transferrin saturation levels initially decreased before returning toward baseline (Figure 5). Ferritin and hepcidin levels also decreased in the daprodustat group over the treatment period. All iron parameters were stable in the placebo group. Few participants in either group received i.v. iron during study treatment, and monthly oral iron dose was also similar between groups (Supplementary Table S6).Table 2Hb- and transfusion-related secondary endpoints (ITT population)OutcomeDaprodustat (n = 307)Placebo (n = 307)Participants with mean EP Hb level 11–12 g/dl n (%)132 (52)17 (8) Difference in response rate [daprodustat – placebo], % (95% CI)45 (37, 52) 1-sided P value< 0.0001Evaluable Hb within Hb 11–12 g/dl target range during EP Mean % time50.18.2 Treatment difference [daprodustat – placebo], % (95% CI)38.8 (25.0, 54.6) 1-sided P value< 0.0001Participants discontinuing randomized treatment due to meeting rescue criteria n (%)2 (<1)26 (8) Incidence rate per 100 PY1.3318.88 Hazard ratio (95% CI)0.07 (0.02, 0.30) 1-sided P value0.0002On-treatment blood transfusions Received transfusion, n (%)4 (1)15 (5) Time to first transfusion, median d10660On-treatment rhEPO use Received rhEPO, n (%)9 (3)22 (7) Time to first rhEPO, median d148115CI, confidence interval; EP, evaluation period; Hb, hemoglobin; ITT, intent-to-treat; PY, patient-years