#3676 EVALUATION OF HAEMOGLOBIN RESPONSE IN PATIENTS WITH CKD-RELATED ANAEMIA NOT ON DIALYSIS RECEIVING DAPRODUSTAT OR CONTROL IN ASCEND-ND

Abstract

Abstract Background and Aims Daprodustat (Dapro) is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated in anaemia of chronic kidney disease (CKD). ASCEND-ND1 achieved non-inferiority (NI) for Dapro vs darbepoetin alfa (Darbe) in both coprimary endpoints, mean change in haemoglobin (Hb) levels from baseline to the evaluation period (EP; Week [Wk] 28–Wk 52) and first occurrence of a composite major adverse cardiovascular event, in patients (pts) with anaemia of CKD not on dialysis. Here, we present key Hb efficacy data and evaluate differences in Hb response within ASCEND-ND subgroups. Method Pts with Stages 3–5 CKD (not on erythropoiesis stimulating agents [ESAs]: Hb 8–10g/dL; on ESAs: Hb 8–11g/dL) were randomised 1:1 to Dapro or Darbe. Statistical analysis methods for the coprimary endpoint have been published.1 Secondary endpoints evaluated during the EP included: 1) the percentage of Hb responders (pts with mean evaluable Hb within the analysis range [10–11.5g/dL]); 2) the percentage of time Hb was within the analysis range; 3) analysis of Hb change from baseline to Wk 52. Secondary endpoints were analysed as follows: 1) Cochran-Mantel-Haenszel test adjusted for ESA use and region; 2) Rosendaal method (evaluable Hb values) and Hodges-Lehmann and stratified Mann-Whitney estimates of treatment effect, analysed with a van Elteren's test stratified by ESA use and region; 3) mixed model repeated measures analysis (on-/off-treatment, observed Hb values from Wks 28–52) with factors for ESA use, region, baseline Hb (by time), treatment by time interactions. Secondary and subgroup analyses were not multiplicity adjusted. Results Of 3872 pts in ASCEND-ND (Dapro n = 1937; Darbe n = 1935), mean baseline Hb levels were similar for both treatment arms and mean change in the EP Hb level for Dapro and Darbe met the prespecified NI margin of ‒0.75 g/dL (difference = 0.08g/dL; 95% confidence interval [CI] = 0.03, 0.13).1 Subgroup analyses were consistent with coprimary analyses (Table), with little or no heterogeneity between most groups: 7/22 subgroups (ethnicity, high-level race, region, ESA use at randomisation, prior ESA dose group, history of stroke, and hospitalisation 6 months prior to screening) had interaction p values <0.1; however, all subgroups met the NI criterion with between-group differences that were not clinically meaningful. Proportions of pts within the Hb analysis range were higher for Dapro than Darbe in the EP overall and regardless of baseline ESA use and similar for region (Table). The median (interquartile range) percentage of time Hb was in the analysis range during the EP was 70.5% (45.3%–93.2%) for Dapro vs 63.2% (33.7%–88.9%) for Darbe. Dapro was associated with a nominally NI (margin of ‒15%) and significant increase in percentage time in analysis range during the EP (estimate of median difference [95% CI] = 4.57% [2.04%, 7.11%]; one-sided p<0.0001). The estimate (95% CI) for the probability that Dapro had a greater percentage of time Hb within the analysis range than Darbe was 0.55 (0.53, 0.57); the lower boundary of the 95% CI exceeded 0.50, representing equal probability between the two treatment arms. Results by region were similar for Dapro vs Darbe (treatment effect): Asia Pacific = 0.56; Eastern Europe/South Africa = 0.51; Western Europe/Canada/Australia/New Zealand/Israel, 0.58; Latin America, 0.58; USA, 0.55). In mixed-model repeated measures analysis, g/dL Hb change (standard error) at Wk 52 was 0.76 (0.029) with Dapro and 0.73 (0.029) with Darbe (difference [95% CI] = 0.03 [−0.05, 0.11]). Hb efficacy was similar regardless of ESA use (Figure). Conclusion Dapro was effective and NI to Darbe for maintaining Hb in non-dialysis pts with anaemia of CKD, and results of subgroup analyses were consistent with the coprimary analyses. Additionally, Dapro raised and maintained Hb within the analysis range regardless of baseline ESA use or region. These preliminary analyses indicated a nominal NI showcasing greater Hb time in range with Dapro vs Darbe; further analyses will be presented to fully characterise this interaction.