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  • 1
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    SP343DAPRODUSTAT MAINTAINS HEMOGLOBIN LEVELS IN CKD SUBJECTS REQUIRING HIGHER ESA DOSES
    Oxford University Press (OUP) ; 2019
    In:  Nephrology Dialysis Transplantation Vol. 34, No. Supplement_1 ( 2019-06-01)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 34, No. Supplement_1 ( 2019-06-01)
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfz103.SP343
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 2
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    The ASCEND-ND trial: study design and participant characteristics
    Oxford University Press (OUP) ; 2022
    In:  Nephrology Dialysis Transplantation Vol. 37, No. 11 ( 2022-10-19), p. 2157-2170
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 37, No. 11 ( 2022-10-19), p. 2157-2170
    Abstract: Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. Methods The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3–5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8–10 g/dL or receiving ESAs with screening Hb of 8–12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28–52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. Results Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin–angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfab318
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    #3676 EVALUATION OF HAEMOGLOBIN RESPONSE IN PATIENTS WITH CKD-RELATED ANAEMIA NOT ON DIALYSIS RECEIVING DAPRODUSTAT OR CONTROL IN ASCEND-ND
    Oxford University Press (OUP) ; 2023
    In:  Nephrology Dialysis Transplantation Vol. 38, No. Supplement_1 ( 2023-06-14)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
    Abstract: 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 & lt;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 & lt;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.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfad063a_3676
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 4
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    P0862DAPRODUSTAT INTERACTION WITH PHOSPHATE BINDERS HAS MINIMAL IMPACT ON HEMOGLOBIN VALUES IN HEMODIALYSIS POPULATION
    Oxford University Press (OUP) ; 2020
    In:  Nephrology Dialysis Transplantation Vol. 35, No. Supplement_3 ( 2020-06-01)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 35, No. Supplement_3 ( 2020-06-01)
    Abstract: Daprodustat is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in phase 3 development for the treatment of anemia of chronic kidney disease (CKD). Phosphate binders (PB) are widely prescribed for hemodialysis (HD) patients to control for hyperphosphatemia. The coadministration of PB and HIF-PHI may potentially impact hemoglobin values thus requiring time between PB administration and HIF-PHI. The purpose of this analysis was to determine whether daprodustat interaction with PB has an impact on hemoglobin (Hgb) values in the HD population. Method GSK PHI113633 study (NCT01977482) included 216 subjects on maintenance HD previously treated with rhEPO. This study included daprodustat dose-ranging for the first 4 weeks, followed by a Hgb correction/maintenance phase for the next 20 weeks; daprodustat was dosed daily without regard to the timing of PB administration. The control group received placebo for 4 weeks, followed by rhEPO for the next 20 weeks as previously reported (Clin Kidney J 2019;12(1):139-148). Target Hgb range was 10.0-11.5 g/dL from Week 4 through Week 24. Baseline PB use was a prespecified study subgroup of interest. The difference in mean Hgb values at Week 24 between treatment groups was summarized overall and by subgroup. Comparisons were performed for the Week 24 Hgb (post hoc), as well as the final dose of daprodustat, for those receiving/not receiving PB. Results The majority of HD subjects in this 24-week safety and efficacy study received PB at baseline; 136 of 177 (77%) of subjects on daprodustat and 33 of 39 (85%) of subjects on control were taking PBs, with comparable phosphate control at baseline [mean (±SD) phosphate: daprodustat 1.76 mmol/L (0.56); control 1.67 mmol/L (0.44)] . No meaningful difference in Hgb change from baseline (CFB) at Week 24 was noted between daprodustat and rhEPO groups (Table 1). Conclusion These results suggest that daprodustat can be taken without regard to the timing of PB administration. Results of the large, phase 3 dialysis study of daprodustat will be important to definitively confirm these initial observations.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfaa142.P0862
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 5
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    #3715 THE EFFECT OF DAPRODUSTAT ON INTRAVENOUS IRON USE IN PATIENTS WITH CKD-RELATED ANAEMIA ON DIALYSIS IN THE ASCEND TRIALS
    Oxford University Press (OUP) ; 2023
    In:  Nephrology Dialysis Transplantation Vol. 38, No. Supplement_1 ( 2023-06-14)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
    Abstract: Intravenous (IV) iron is frequently needed in patients with chronic kidney disease (CKD) to ensure sufficient iron is available for erythropoiesis. However high doses of IV iron and erythropoiesis stimulating agents (ESAs) may be associated with risks in these patients [1]. The hypoxia-inducible factor-prolyl hydroxylase domain inhibitor daprodustat was non-inferior to comparator ESAs for the primary endpoint of efficacy (change-in-Hb) in the multicentre, randomised, Phase 3 trials ASCEND-D (NCT02879305) [2] and ASCEND-TD (NCT03400033) [3], also for the safety (major adverse cardiovascular [CV] events) coprimary endpoint in ASCEND-D [2]. This analysis of ASCEND-D and ASCEND-TD compared daprodustat t o active ESAs on measures of IV iron use in dialysis patients. Method Daprodustat and ESAs were compared in patients with CKD anaemia on haemodialysis/peritoneal dialysis (ASCEND-D); haemodialysis (ASCEND-TD). ASCEND-D (N = 2,964) was an open-label CV outcome study using daprodustat once daily, while ASCEND-TD (N = 407) was a double-blind, double-dummy, 52-week study investigating three times weekly dosing of daprodustat. In both studies, following randomisation, treatment dosage was titrated to achieve the Hb target range of 10.0–11.0g/dL, with Hb efficacy assessed during the evaluation period (EP), Weeks 28–52. All patients were required to have ferritin & gt;100 ng/mL and/or transferrin saturation (TSAT) & gt;20% at baseline for inclusion. Throughout the study, iron therapy was administered if ferritin was ≤100 ng/mL and/or TSAT was ≤20% so patients would remain iron replete throughout the study. Investigators chose the route and dose of iron administration per patient iron status and clinical judgement. Stopping threshold criteria of 800 ng/mL ferritin + TSAT & gt;20%, or TSAT & gt;40% were implemented to avoid iron overload, but investigators could stop administration of iron at levels below the protocol-defined stopping thresholds. The average monthly IV iron dose (mg)/patient to Week 52 was a principal secondary endpoint, while the proportion of patients who met iron management criteria with a decrease in monthly IV iron dose during the EP relative to baseline and until patients received first transfusion were exploratory endpoints. The baseline monthly IV iron dose was defined as the average monthly IV iron (mg) over the 16 weeks prior to randomisation for ASCEND-D and over the 12 weeks prior to randomisation for ASCEND-TD. Results The proportion of patients with IV iron use at baseline was similar in both treatment arms for ASCEND-D (64%) but lower in the daprodustat group in ASCEND-TD (63% vs 72% in the ESA group). In both studies the proportion of patients receiving IV iron during the EP decreased (ASCEND-D: daprodustat 49%, ESA 52%; ASCEND-TD: daprodustat 38%, ESA 40%). The average monthly IV iron dose during the EP and from Day 1 to Week 52 was lower than monthly IV iron dose at baseline, however daprodustat was not associated with a statistically significant reduction in monthly IV iron per patient to Week 52 vs ESA comparator (Table 1). After a period of IV iron requirements decreasing, based on adjustment to protocol-specified levels, IV iron dosage remained relatively stable for daprodustat and ESA (Figure 1). In ASCEND-D, 3 of 23 pre-defined subgroups (prior ESA dose group, ESA hyporesponders2, history of myocardial infarction) showed a trend towards heterogeneity (interaction p-value & lt;0.1), with differences in monthly IV iron use in the prior ESA dose group receiving ≥7000 U/week (-21.2 mg/month) and in the ESA hyporesponder group (-31.7 mg/month) in favour of daprodustat. Fewer patients met the criteria for stopping iron while on daprodustat vs ESA, whereas the converse was observed in ASCEND-TD (Table 1). Conclusion In ASCEND-D and -TD, no clinically or statistically significant reduction in monthly IV iron use was seen with daprodustat vs ESA comparators, although there was a numerical decrease in the proportion of patients receiving IV iron during the EP for the daprodustat group in both studies.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfad063c_3715
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 6
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    MO530: Daprodustat is not Associated With an Increased Risk of Cancer: Results From the ASCEND-D and ASCEND-ND Trials
    Oxford University Press (OUP) ; 2022
    In:  Nephrology Dialysis Transplantation Vol. 37, No. Supplement_3 ( 2022-05-03)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 37, No. Supplement_3 ( 2022-05-03)
    Abstract: Increased HIF-1 levels are associated with mortality in some cancer patients, and levels of HIF-1 may also impact response to cancer treatments. Use of recombinant human erythropoietin or its analogs [erythropoiesis-stimulating agents (ESA)] in clinical trials in patients with cancer has been associated with increased risk of cancer-related morbidity and mortality, though the mechanism(s) for these effects is not clear. Daprodustat is an oral hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor that increases the secretion of endogenous erythropoietin and the production of red cells. Cardiovascular outcome trials in patients with anemia of chronic kidney disease (CKD) requiring dialysis (ASCEND-D [1] ; NCT02879305) and those not on dialysis (ASCEND-ND [2]; NCT028768355) have recently been published. Given the long latency with cancer events, we explored the effect of daprodustat as compared with ESA on the risk of cancer development utilizing a post-hoc modified intention-to-treat (mITT) approach, which includes events on and off treatment and provides greater protection to randomization than on-treatment approaches. METHOD Cancer-related adverse events (AEs) from the ASCEND studies were identified based on a predefined list of terms that included new cancer events or tumor progression and recurrence for patients receiving at least one dose of daprodustat or ESA (Safety Population). Patients were included into these trials as long as they had no history of cancer within 2 years prior to screening, were not currently receiving treatment for cancer and did not have a complicated kidney cyst. In addition to reporting the number and percentage of patients with cancer AEs, overall and by types, the rate per 100 person-year (PY) is also provided given differential follow-up for patients in these trials. RESULTS A total of 2964 patients were randomized in ASCEND-D and 3872 in ASCEND-ND, with ∼14 200 PY of follow-up. At baseline, patients reported a past history of cancer in 5.0% and 4.9% of patients receiving daprodustat or ESA, respectively, in ASCEND-D; and in 5.2% and 4.4% of patients receiving daprodustat or darbepoetin alfa, respectively, in ASCEND-ND. In the Safety Population, both the rate of cancer-related AEs and the rate per 100 PY were balanced for each study, with no pattern emerging regarding location or type (Table 1). Of the patients with overall cancer AEs in the Safety Population (Table 1), fatal AEs in ASCEND-D occurred in 11 patients receiving daprodustat and in 15 patients receiving ESA, which was  & lt;1% and 1% of the Safety Population, respectively. In ASCEND-ND, fatal AEs occurred in 6 patients receiving daprodustat and 11 patients receiving darbepoetin alfa, which was  & lt;1% of the Safety Population in both groups. Pooling of data from the D and ND studies also demonstrated balance in cancer events between the dapro and ESA arms. Further analysis of the characteristics of patients with cancer AEs demonstrated that the number of patients with multiple events, the time to first onset and outcome of the event and event seriousness and severity were also similar between treatment groups for both trials. CONCLUSION In cardiovascular outcome trials comprised of patients requiring dialysis (ASCEND-D) and not requiring dialysis (ASCEND-ND) with anemia of CKD, daprodustat was not associated with an increased risk of cancer, or cancer mortality, relative to ESA. Collectively, across these trials, cancer AEs are balanced.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfac072.012
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    SaO004OCULAR SAFETY PROFILE OF DAPRODUSTAT: RESULTS OF TWO 24 WEEK STUDIES
    Oxford University Press (OUP) ; 2018
    In:  Nephrology Dialysis Transplantation Vol. 33, No. suppl_1 ( 2018-05-01), p. i316-i316
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 33, No. suppl_1 ( 2018-05-01), p. i316-i316
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfy104.SaO004
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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  • 8
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    Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants with chronic kidney disease
    Oxford University Press (OUP) ; 2019
    In:  Clinical Kidney Journal Vol. 12, No. 1 ( 2019-02-01), p. 129-138
    Details
    In: Clinical Kidney Journal, Oxford University Press (OUP), Vol. 12, No. 1 ( 2019-02-01), p. 129-138
    Type of Medium: Online Resource
    ISSN: 2048-8505 , 2048-8513
    URL: Article
    DOI: 10.1093/ckj/sfy013
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 9
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    #3704 EU REGION-SPECIFIC CARDIOVASCULAR EVENT DATA FOR DAPRODUSTAT IN ASCEND-D AND ASCEND-ND
    Oxford University Press (OUP) ; 2023
    In:  Nephrology Dialysis Transplantation Vol. 38, No. Supplement_1 ( 2023-06-14)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
    Abstract: Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor under investigation for the treatment of anaemia of chronic kidney disease. Phase 3 studies in dialysis (ASCEND-D) and non-dialysis (ASCEND-ND) patients demonstrated the non-inferiority of daprodustat vs recombinant human erythropoietin (rhEPO) control (in ASCEND-D) or darbepoetin alfa (ASCEND-ND) control in terms of the mean change in haemoglobin levels between Weeks 28 and 52 versus baseline and the first occurrence of a composite major adverse cardiovascular (CV) event (MACE) [1, 2]. Post-hoc analyses were conducted to evaluate prespecified CV endpoints for patients enrolled in these studies from participating countries in Europe (EU patients) versus elsewhere (non-EU patients). Method Post-hoc time to the first adjudicated MACE (death from any cause, non-fatal myocardial infarction or non-fatal stroke), time to the first adjudicated MACE or thromboembolic event (TEE; deep vein thrombosis, pulmonary embolism or vascular access thrombosis), and time to the first adjudicated MACE or hospitalisation for heart failure (HHF) were analysed for EU (enrolled from Austria, Belgium, Bulgaria, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Spain, Sweden and the UK; not all countries participated in both studies) and non-EU (all other participating countries) patients. Hazard ratios (HRs) and associated 95% confidence intervals were calculated to evaluate the likelihood of CV events with daprodustat versus alternative therapy in both studies. HRs for EU and non-EU patients were compared for each endpoint in each study and p-values were calculated to assess the statistical significance of observed differences. Significance was defined at the 10% level (interaction p-value & lt;0.1). Results ASCEND-D included 415 EU patients and 1072 non-EU patients randomised to daprodustat, and 440 EU and 1037 non-EU patients randomised to rhEPO. ASCEND-ND included 410 EU patients and 1527 non-EU patients randomised to daprodustat, and 407 EU and 1528 non-EU patients randomised to darbepoetin alfa. No significant heterogeneity was observed between EU and non-EU patients in terms of the prespecified CV endpoints (p≥0.1979). In ASCEND-D and ASCEND-ND, the results for MACE, MACE+TEE and MACE+HHF for the EU subgroup were consistent with the non-EU subgroup (Table), as well as with the co-primary analysis [1, 2]. Efficacy and additional safety data for EU versus non-EU patients are being explored and will be included in the subsequent presentation. Conclusion Non-inferiority in terms of the first occurrence of MACE was demonstrated for daprodustat versus rhEPO in ASCEND-D and versus darbepoetin alfa in ASCEND-ND.1,2 Results for EU and non-EU patients in the current analysis were consistent with the global outcomes from both studies.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfad063c_3704
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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    MO559ASCEND-ND: STUDY DESIGN AND BASELINE CHARACTERISTICS
    Oxford University Press (OUP) ; 2021
    In:  Nephrology Dialysis Transplantation Vol. 36, No. Supplement_1 ( 2021-05-29)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 36, No. Supplement_1 ( 2021-05-29)
    Abstract: The Anemia Study in Chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Non-Dialysis (ASCEND-ND; NCT02876835) trial is evaluating the efficacy and safety of daprodustat when compared with darbepoetin alfa in CKD patients with anaemia not requiring dialysis. We report the trial design as well as key baseline characteristics of participants. Method Eligible patients from 39 countries were adults with CKD stages 3–5 who were able to provide informed consent and demonstrated adherence to daprodustat placebo tablets and study procedures during the run-in period. Patients were eligible if (1) they were not using erythropoiesis stimulating agents (ESAs) and had a screening haemoglobin (Hb) 8 to 10 g/dL or if (2) they were receiving ESAs with screening Hb of 8 to 12 g/dL. Patients were required to be iron replete [transferrin saturation (TSAT) & gt;20% and serum ferritin & gt;100 ng/mL] at screening. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open-label (sponsor-blind) trial design with blinded endpoint assessment. An IDMC conducts regular reviews of unblinded safety and efficacy data and makes recommendations for additions or adjustments. An external, independent and blinded Clinical Events Classification (CEC) group, led by the Duke Clinical Research Institute, in collaboration with George Clinical, adjudicate predefined events. During the study, both groups had randomised treatment adjusted using a protocol-defined algorithm targeting a Hb range of 10 to 11 g/dL. Participants also followed protocol-defined iron management criteria to ensure they remained iron replete. Additionally, an anaemia rescue algorithm was in place to minimise the risk of extended periods of inadequate Hb response and to ensure consistent application of rescue therapy across the study. The co-primary endpoints are mean change in Hb between baseline and Evaluation Period (EP; Weeks 28 to 52, inclusive) and time to first adjudicated major adverse cardiovascular event (MACE; composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke). The study has more than 99% power for the Hb non-inferiority (NI) test with an NI margin of -0.75 g/dL for the treatment difference of mean change in Hb between baseline and EP, and approximately 90% power to exclude the NI margin of 1.25 for time to first adjudicated MACE, for daprodustat compared with darbepoetin alfa. Conditional on both co-primary endpoints achieving NI at the one-sided 2.5% level, statistical testing will progress to evaluate MACE and the principal secondary endpoint of CKD progression for superiority. These tests will be multiplicity adjusted. Results A total of 3872 patients were randomised (median age 67 years, 56% female; 55% white, 28% Asian, and 10% black). The median baseline Hb was 9.8 g/dL, serum ferritin was 274 ng/mL, TSAT 30%, and eGFR 18 mL/min/1.73 m2. Among randomised patients, 54% were ESA non-users, 57% reported a history of diabetes mellitus and 36% a history of cardiovascular disease. Median blood pressure was 135/74 mmHg. Sixty percent of participants were taking angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, while 57% were taking lipid modifying agents at baseline. The trial is expected to complete during 2021. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not requiring dialysis.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfab085.0022
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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