| Objectives . | Endpoints . |
|---|---|
| Co-primary objectives | Co-primary endpoints (tested in parallel for non-inferiority) |
| • To compare daprodustat with darbepoetin alfa for CV safety (non inferiority) | • Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke) |
| • To compare daprodustat with darbepoetin alfa for Hb efficacy (non inferiority) | • Mean change in Hb between baseline and EP (mean over Weeks 28 to 52) |
| Principal secondary objectives | Principal secondary endpoints(tested for superiority, adjusted for multiplicity) |
| • To compare daprodustat with darbepoetin alfa on CV safety endpoints | • Time to first occurrence of adjudicated - MACE - MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) - MACE or a hospitalization for heart failure |
| • To compare daprodustat with darbepoetin alfa on the progression of CKD | • Time to progression of CKDa |
| Secondary objectives | Secondary endpoints(tested for superiorityb, no multiplicity adjustment) |
| • To compare daprodustat with darbepoetin alfa on additional CV safety endpoints | • All-cause mortality, CV mortality, fatal or non-fatal MI, fatal or non-fatal strokec • MACE or hospitalization for heart failurec (recurrent events analysis) • CV mortality or non-fatal MIc • All-cause hospitalization • All-cause hospital re-admission within 30 days • MACE or hospitalization for heart failure or thromboembolic eventsc • Hospitalization for heart failurec • Thromboembolic eventsc • Individual components of CKD progressionc |
| • To compare daprodustat with darbepoetin alfa on Hb variability | • Hb change from baseline to Week 52b • N (%) responders, defined as mean Hb within the Hb analysis range 10–11.5 g/dL during EPd |
| • Percent time Hb in analysis range (10–11.5 g/dL) during the evaluation period (EP, Weeks 28–52) and during the maintenance phase (MP; Weeks 28 to end of trial) (non-inferiority analysis that will use a margin of 15% less time in range)b | |
| • To compare daprodustat with darbepoetin alfa on BP | • Change from baseline in SBP, DBP and MAP at Week 52 and at end of treatment • Number of BP exacerbation events per 100 patient-years • N (%) with at least one BP exacerbation event during study |
| • To compare daprodustat with darbepoetin alfa on the time to rescue (defined as permanently stopping randomized treatment due to meeting rescue criteria) | • Time to stopping randomized treatment due to meeting rescue criteria |
| • To compare daprodustat with darbepoetin alfa on HRQoL and utility score | • Mean change in SF-36 HRQoL scores (PCS, MCS and eight health domains) between baseline and Weeks 8, 12, 28 and 52; of particular interest are the changes from baseline in the vitality and physical functioning domains at Week 28 and 52. • Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 • Change from baseline in EQ VAS at Week 52 |
| • To compare daprodustat with darbepoetin alfa on the symptom severity and change | • Change from Baseline at Weeks 8, 12, 28 and 52 by domain and overall symptom score on the CKD-AQ • Change from Baseline at Week 8,12, 28 and 52 in PGI-S |
| Objectives . | Endpoints . |
|---|---|
| Co-primary objectives | Co-primary endpoints (tested in parallel for non-inferiority) |
| • To compare daprodustat with darbepoetin alfa for CV safety (non inferiority) | • Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke) |
| • To compare daprodustat with darbepoetin alfa for Hb efficacy (non inferiority) | • Mean change in Hb between baseline and EP (mean over Weeks 28 to 52) |
| Principal secondary objectives | Principal secondary endpoints(tested for superiority, adjusted for multiplicity) |
| • To compare daprodustat with darbepoetin alfa on CV safety endpoints | • Time to first occurrence of adjudicated - MACE - MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) - MACE or a hospitalization for heart failure |
| • To compare daprodustat with darbepoetin alfa on the progression of CKD | • Time to progression of CKDa |
| Secondary objectives | Secondary endpoints(tested for superiorityb, no multiplicity adjustment) |
| • To compare daprodustat with darbepoetin alfa on additional CV safety endpoints | • All-cause mortality, CV mortality, fatal or non-fatal MI, fatal or non-fatal strokec • MACE or hospitalization for heart failurec (recurrent events analysis) • CV mortality or non-fatal MIc • All-cause hospitalization • All-cause hospital re-admission within 30 days • MACE or hospitalization for heart failure or thromboembolic eventsc • Hospitalization for heart failurec • Thromboembolic eventsc • Individual components of CKD progressionc |
| • To compare daprodustat with darbepoetin alfa on Hb variability | • Hb change from baseline to Week 52b • N (%) responders, defined as mean Hb within the Hb analysis range 10–11.5 g/dL during EPd |
| • Percent time Hb in analysis range (10–11.5 g/dL) during the evaluation period (EP, Weeks 28–52) and during the maintenance phase (MP; Weeks 28 to end of trial) (non-inferiority analysis that will use a margin of 15% less time in range)b | |
| • To compare daprodustat with darbepoetin alfa on BP | • Change from baseline in SBP, DBP and MAP at Week 52 and at end of treatment • Number of BP exacerbation events per 100 patient-years • N (%) with at least one BP exacerbation event during study |
| • To compare daprodustat with darbepoetin alfa on the time to rescue (defined as permanently stopping randomized treatment due to meeting rescue criteria) | • Time to stopping randomized treatment due to meeting rescue criteria |
| • To compare daprodustat with darbepoetin alfa on HRQoL and utility score | • Mean change in SF-36 HRQoL scores (PCS, MCS and eight health domains) between baseline and Weeks 8, 12, 28 and 52; of particular interest are the changes from baseline in the vitality and physical functioning domains at Week 28 and 52. • Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 • Change from baseline in EQ VAS at Week 52 |
| • To compare daprodustat with darbepoetin alfa on the symptom severity and change | • Change from Baseline at Weeks 8, 12, 28 and 52 by domain and overall symptom score on the CKD-AQ • Change from Baseline at Week 8,12, 28 and 52 in PGI-S |
BP, blood pressure; CKD-AQ, Chronic Kidney Disease-Anaemia Questionnaire; CV, cardiovascular; DBP, diastolic BP; EP, evaluation phase; EQ-5D-5L, EuroQoL 5-dimension 5-level; EQ VAS, EuroQoL visual analogue scale; Hb, haemoglobin; HRQoL, health-related quality of life; MACE, major adverse cardiac event; MAP, mean arterial pressure; MCS, mental component score; MP, maintenance phase; PCS, physical component score; PGI-S, patient global impression of severity; SBP, systolic BP; SF-36, 36-item Short Form.
Conversion factor from g/dL to g/L is 10 and from g/dL to mmol/L is 0.6206 (e.g. Hb of 10–11 g/dL is equivalent to 100–110 g/L or 6.2–6.8 mmol/L).
Progression of CKD defined as 40% decline in eGFR from baseline (confirmed 4–13 weeks later) or end-stage renal disease as defined by initiating chronic dialysis for ≥90 days or not initiating chronic dialysis when dialysis is indicated or kidney transplantation.
Hb change from baseline to Week 52 is tested for non-inferiority using the −0.75 g/dL margin used in the co-primary analysis. % time in range is tested first for non-inferiority, then for superiority.
Events adjudicated; for CKD progression only, two components to be adjudicated.
To account for within-subject variability, 0.5 g/dL was added to the upper end of the target range to create a defined analysis range of 10.0–11.5 g/dL.
| Objectives . | Endpoints . |
|---|---|
| Co-primary objectives | Co-primary endpoints (tested in parallel for non-inferiority) |
| • To compare daprodustat with darbepoetin alfa for CV safety (non inferiority) | • Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke) |
| • To compare daprodustat with darbepoetin alfa for Hb efficacy (non inferiority) | • Mean change in Hb between baseline and EP (mean over Weeks 28 to 52) |
| Principal secondary objectives | Principal secondary endpoints(tested for superiority, adjusted for multiplicity) |
| • To compare daprodustat with darbepoetin alfa on CV safety endpoints | • Time to first occurrence of adjudicated - MACE - MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) - MACE or a hospitalization for heart failure |
| • To compare daprodustat with darbepoetin alfa on the progression of CKD | • Time to progression of CKDa |
| Secondary objectives | Secondary endpoints(tested for superiorityb, no multiplicity adjustment) |
| • To compare daprodustat with darbepoetin alfa on additional CV safety endpoints | • All-cause mortality, CV mortality, fatal or non-fatal MI, fatal or non-fatal strokec • MACE or hospitalization for heart failurec (recurrent events analysis) • CV mortality or non-fatal MIc • All-cause hospitalization • All-cause hospital re-admission within 30 days • MACE or hospitalization for heart failure or thromboembolic eventsc • Hospitalization for heart failurec • Thromboembolic eventsc • Individual components of CKD progressionc |
| • To compare daprodustat with darbepoetin alfa on Hb variability | • Hb change from baseline to Week 52b • N (%) responders, defined as mean Hb within the Hb analysis range 10–11.5 g/dL during EPd |
| • Percent time Hb in analysis range (10–11.5 g/dL) during the evaluation period (EP, Weeks 28–52) and during the maintenance phase (MP; Weeks 28 to end of trial) (non-inferiority analysis that will use a margin of 15% less time in range)b | |
| • To compare daprodustat with darbepoetin alfa on BP | • Change from baseline in SBP, DBP and MAP at Week 52 and at end of treatment • Number of BP exacerbation events per 100 patient-years • N (%) with at least one BP exacerbation event during study |
| • To compare daprodustat with darbepoetin alfa on the time to rescue (defined as permanently stopping randomized treatment due to meeting rescue criteria) | • Time to stopping randomized treatment due to meeting rescue criteria |
| • To compare daprodustat with darbepoetin alfa on HRQoL and utility score | • Mean change in SF-36 HRQoL scores (PCS, MCS and eight health domains) between baseline and Weeks 8, 12, 28 and 52; of particular interest are the changes from baseline in the vitality and physical functioning domains at Week 28 and 52. • Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 • Change from baseline in EQ VAS at Week 52 |
| • To compare daprodustat with darbepoetin alfa on the symptom severity and change | • Change from Baseline at Weeks 8, 12, 28 and 52 by domain and overall symptom score on the CKD-AQ • Change from Baseline at Week 8,12, 28 and 52 in PGI-S |
| Objectives . | Endpoints . |
|---|---|
| Co-primary objectives | Co-primary endpoints (tested in parallel for non-inferiority) |
| • To compare daprodustat with darbepoetin alfa for CV safety (non inferiority) | • Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke) |
| • To compare daprodustat with darbepoetin alfa for Hb efficacy (non inferiority) | • Mean change in Hb between baseline and EP (mean over Weeks 28 to 52) |
| Principal secondary objectives | Principal secondary endpoints(tested for superiority, adjusted for multiplicity) |
| • To compare daprodustat with darbepoetin alfa on CV safety endpoints | • Time to first occurrence of adjudicated - MACE - MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) - MACE or a hospitalization for heart failure |
| • To compare daprodustat with darbepoetin alfa on the progression of CKD | • Time to progression of CKDa |
| Secondary objectives | Secondary endpoints(tested for superiorityb, no multiplicity adjustment) |
| • To compare daprodustat with darbepoetin alfa on additional CV safety endpoints | • All-cause mortality, CV mortality, fatal or non-fatal MI, fatal or non-fatal strokec • MACE or hospitalization for heart failurec (recurrent events analysis) • CV mortality or non-fatal MIc • All-cause hospitalization • All-cause hospital re-admission within 30 days • MACE or hospitalization for heart failure or thromboembolic eventsc • Hospitalization for heart failurec • Thromboembolic eventsc • Individual components of CKD progressionc |
| • To compare daprodustat with darbepoetin alfa on Hb variability | • Hb change from baseline to Week 52b • N (%) responders, defined as mean Hb within the Hb analysis range 10–11.5 g/dL during EPd |
| • Percent time Hb in analysis range (10–11.5 g/dL) during the evaluation period (EP, Weeks 28–52) and during the maintenance phase (MP; Weeks 28 to end of trial) (non-inferiority analysis that will use a margin of 15% less time in range)b | |
| • To compare daprodustat with darbepoetin alfa on BP | • Change from baseline in SBP, DBP and MAP at Week 52 and at end of treatment • Number of BP exacerbation events per 100 patient-years • N (%) with at least one BP exacerbation event during study |
| • To compare daprodustat with darbepoetin alfa on the time to rescue (defined as permanently stopping randomized treatment due to meeting rescue criteria) | • Time to stopping randomized treatment due to meeting rescue criteria |
| • To compare daprodustat with darbepoetin alfa on HRQoL and utility score | • Mean change in SF-36 HRQoL scores (PCS, MCS and eight health domains) between baseline and Weeks 8, 12, 28 and 52; of particular interest are the changes from baseline in the vitality and physical functioning domains at Week 28 and 52. • Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 • Change from baseline in EQ VAS at Week 52 |
| • To compare daprodustat with darbepoetin alfa on the symptom severity and change | • Change from Baseline at Weeks 8, 12, 28 and 52 by domain and overall symptom score on the CKD-AQ • Change from Baseline at Week 8,12, 28 and 52 in PGI-S |
BP, blood pressure; CKD-AQ, Chronic Kidney Disease-Anaemia Questionnaire; CV, cardiovascular; DBP, diastolic BP; EP, evaluation phase; EQ-5D-5L, EuroQoL 5-dimension 5-level; EQ VAS, EuroQoL visual analogue scale; Hb, haemoglobin; HRQoL, health-related quality of life; MACE, major adverse cardiac event; MAP, mean arterial pressure; MCS, mental component score; MP, maintenance phase; PCS, physical component score; PGI-S, patient global impression of severity; SBP, systolic BP; SF-36, 36-item Short Form.
Conversion factor from g/dL to g/L is 10 and from g/dL to mmol/L is 0.6206 (e.g. Hb of 10–11 g/dL is equivalent to 100–110 g/L or 6.2–6.8 mmol/L).
Progression of CKD defined as 40% decline in eGFR from baseline (confirmed 4–13 weeks later) or end-stage renal disease as defined by initiating chronic dialysis for ≥90 days or not initiating chronic dialysis when dialysis is indicated or kidney transplantation.
Hb change from baseline to Week 52 is tested for non-inferiority using the −0.75 g/dL margin used in the co-primary analysis. % time in range is tested first for non-inferiority, then for superiority.
Events adjudicated; for CKD progression only, two components to be adjudicated.
To account for within-subject variability, 0.5 g/dL was added to the upper end of the target range to create a defined analysis range of 10.0–11.5 g/dL.
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