Anemia Study in Chronic Kidney Disease (CKD) : Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat -Forearm Blood Flow (ASCEND-FBF)

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Terminated

CT.gov ID

NCT03446612

Collaborator

(none)

Enrollment

Locations

Arms

4.6

Actual Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Daprodustat has demonstrated an ability to effectively raise hemoglobin concentrations with lower erythropoietin (EPO) levels than those observed after administration of recombinant human erythropoietin (rhEPOs). Therefore, daprodustat has the potential to treat anemia of chronic kidney disease (CKD) with a lower cardiovascular (CV) risk than is observed with the rhEPOs. While the effect of rhEPOs on endothelial function has been assessed, to date the effect of daprodustat or other prolyl hydroxylase inhibitor (PHI) compounds on endothelial function has not. Therefore, the purpose of this study is to compare the effect of daprodustat to darbepoetin alfa on endothelial function by assessing FBF in participants with anemia of CKD by using venous occlusion plethysmography as a means to estimate the potential for daprodustat to have a lower risk of CV events as compared to rhEPO.

This study will use a randomized, repeat dose, open label, parallel group design, in adult, not on-dialysis, male and female participants with anemia of CKD that are currently not treated with rhEPOs.

The study will comprise of three study periods: a screening period starting up to 30 days prior to Day 1, a 42 day (6 week) treatment period, and a follow-up visit up to 14 days later. The total duration of participants involvement is up to 14 weeks (including screening and follow up visit). Approximately 50 participants will be randomized to either daprodustat or darbepoetin alfa.

Condition or Disease	Intervention/Treatment	Phase
Anaemia	Drug: Daprodustat Drug: Darbepoetin alfa Drug: Acetylcholine Drug: Sodium nitroprusside Drug: L-N-monomethyl arginine acetate (L-NMMA)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomized to either daprodustat or darbepoetin alfa. A central randomization approach will be used with stratification by center.Participants will be randomized to either daprodustat or darbepoetin alfa. A central randomization approach will be used with stratification by center.

Masking:

None (Open Label)

Masking Description:

This is an open-label study. However, a central FBF reader, who will read and evaluate the FBF data, will be blinded to the treatment assignment.

Primary Purpose:

Treatment

Official Title:

A Randomized, Repeat Dose, Open Label, Parallel Group, Multi-center Study to Evaluate the Effect of Daprodustat Compared to Darbepoetin Alfa on Forearm Blood Flow in Participants With Anemia of Chronic Kidney Disease That Are Not Dialysis Dependent

Actual Study Start Date :

Jan 10, 2019

Actual Primary Completion Date :

May 29, 2019

Actual Study Completion Date :

May 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Participants receiving Daprodustat Participants will receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Drug: Daprodustat Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food. Drug: Acetylcholine Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. Drug: Sodium nitroprusside Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. Drug: L-N-monomethyl arginine acetate (L-NMMA) L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.
Active Comparator: Participants receiving Darbepoetin alfa Participants will receive Darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).	Drug: Darbepoetin alfa Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks. Drug: Acetylcholine Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. Drug: Sodium nitroprusside Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm. Drug: L-N-monomethyl arginine acetate (L-NMMA) L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Arm

Intervention/Treatment

Experimental: Participants receiving Daprodustat

Participants will receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.

Drug: Daprodustat

Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food.

Drug: Acetylcholine

Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Drug: Sodium nitroprusside

Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Drug: L-N-monomethyl arginine acetate (L-NMMA)

L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Active Comparator: Participants receiving Darbepoetin alfa

Participants will receive Darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).

Drug: Darbepoetin alfa

Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks.

Drug: Acetylcholine

Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Drug: Sodium nitroprusside

Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Drug: L-N-monomethyl arginine acetate (L-NMMA)

L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Outcome Measures

Primary Outcome Measures

Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42) [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine (ACH) was infused intra-arterially at 7.5, 15 and 30 micrograms/minute (ug/min) each for 6 minutes per infusion. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.

Secondary Outcome Measures

Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to acetylcholine is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine.
Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42) [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.
Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to sodium nitroprusside is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside.
Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42) [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 micromoles per minute (umol/min) each infused for 6 minutes into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.
Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA [Day 1 to Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to L-NMMA is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA.
Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with daprodustat.
Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with daprodustat.
Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with daprodustat.
Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with darbepoetin alfa.
Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with darbepoetin alfa.
Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa [Day 1 and Day 42]
Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with darbepoetin alfa.
Change in Augmentation Index (AIx) From Day 1 to 42 [Day 1 to Day 42]
Pulse wave analysis (PWA) is a reproducible, noninvasive method for assessing AIx (a measure of the contribution that wave reflection makes to the arterial pressure waveform). The amplitude and timing of the reflected wave ultimately depends on the stiffness of the small (pre-resistance) vessels and large arteries, and thus, AIx provides a measure of systemic arterial stiffness. A high-fidelity micro manometer was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the radial artery of the dominant arm using gentle pressure. AIx was defined as the augmentation (difference between systolic peaks) expressed as a percentage of the overall pulse pressure. Data for change in AIx from Day 1 to 42 was presented.
Change in Pulse Wave Velocity (PWV) From Day 1 to Day 42 [Day 1 to Day 42]
PWV was assessed with a high-fidelity micro manometer which was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the carotid and femoral arteries as the two points of measure. Data for change in PWV from Day 1 to 42 was presented.
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 59 days]
An AE is any untoward medical occurrence in a clinical study participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/birth effect.
Number of Participants With Any AE of Special Interest (AESI) [Up to 59 days]
AESIs were identified based on non-clinical studies with daprodustat, clinical experience with recombinant human erythropoietins (rhEPOs), and current information regarding hypoxia-inducible factor (HIF)-regulated pathways in mediating hypoxia-associated pathophysiology. The AESIs for daprodustat were identified as follows: Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis; Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular access; Cardiomyopathy; Pulmonary artery hypertension; Cancer-related mortality and tumor progression and recurrence Esophageal and gastric erosions; Proliferative retinopathy, macular edema, choroidal neovascularization; Exacerbation of rheumatoid arthritis and Worsening of hypertension.
Number of Participants Discontinuing the Randomized Study Treatment [Up to Day 42]
Number of participants who discontinued the randomized study treatment were assessed.

Other Outcome Measures

Absolute Values of Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) [Days 1, 14, 28, 42 and 59]
DBP and SBP were measured in a semi-supine position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Change From Baseline in DBP and SBP [Baseline (Day 1) and at Days 14, 28, 42 and 59]
DBP and SBP were measured in a semi-supine position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Electrocardiogram (ECG) Mean Heart Rate [Days 1, 42 and 59]
Full 12-lead ECG were recorded with the participant in a semi-supine position to measure heart rate.
Change From Baseline in ECG Mean Heart Rate [Baseline (Day 1) and at Days 42 and 59]
Full 12-lead ECG were recorded with the participant in a semi-supine position to measure heart rate. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of ECG Parameters- PR Interval, QRS Interval, and QT Interval and QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB) [Days 1, 42 and 59]
Full 12-lead ECGs were recorded with the participant in a semi-supine position to measure PR interval, QRS duration, QT interval and QTcB, calculated (machine read or manually).
Change From Baseline in ECG Parameters- PR Interval, QRS Duration, and QT Interval and QTcB [Baseline (Day 1) and at Days 42 and 59]
Full 12-lead ECGs were recorded with the participant in a semi-supine position to measure PR interval, QRS duration, QT (uncorrected) interval and QTcB, calculated (machine read or manually). Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameters of Platelet Count, White Blood Cell (WBC) Count (Absolute), Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including platelet count, leukocytes, basophils, eosinophils, lymphocytes, monocytes and neutrophils.
Change From Baseline in Hematology Parameters of Platelet Count, Leukocytes, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including platelet count, WBC count (Absolute), basophils, eosinophils, lymphocytes, monocytes and neutrophils. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameter of Red Blood Cell (RBC) Count and Reticulocyte Count (RC) [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including RBC count and RC.
Change From Baseline in Hematology Parameters of RBC Count and RC [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including RBC count and RC. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameters of Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including hemoglobin and MCHC.
Change From Baseline in Hematology Parameters- Hemoglobin and MCHC [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including hemoglobin and MCHC. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Hematology Parameter: Hematocrit [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including hematocrit.
Change From Baseline in Hematology Parameter: Hematocrit [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including hematocrit. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Hematology Parameter of Red Blood Cell Distribution Width (RDW) [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including RDW.
Change From Baseline in RDW [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including RDW. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameter of Mean Corpuscular Hemoglobin (MCH) [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including MCH.
Change From Baseline in Hematology Parameter of MCH [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including MCH. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of the Hematology Parameter of Mean Corpuscular Volume (MCV) [Days 1, 42 and 59]
Blood samples were collected for the analysis of hematology parameters including MCV.
Change From Baseline in Hematology Parameter of MCV [Baseline (Day 1) and at Days 42 and 59]
Blood samples were collected for the analysis of hematology parameters including MCV. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Clinical Chemistry Parameters of Sodium, Potassium, Carbon-dioxide (Total), Chloride, Glucose and Urea [Days 1, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; sodium, potassium, carbon-dioxide (total), chloride, glucose and urea.
Change From Baseline in Clinical Chemistry Parameter: Sodium, Potassium, Carbon-dioxide (Total), Chloride, Glucose and Urea [Baseline (Day 1) and at Days 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; sodium, potassium, carbon-dioxide (total), chloride, glucose and urea. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Clinical Chemistry Parameters of Creatinine [Days 1, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine.
Change From Baseline in Clinical Chemistry Parameter: Creatinine [Baseline (Day 1) and at Days 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Clinical Chemistry Parameters of Bilirubin (Direct/Indirect and Total) [Days 1, 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; bilirubin (direct/indirect and total).
Change From Baseline in Clinical Chemistry Parameter: Bilirubin (Direct/Indirect and Total) [Baseline (Day 1) and at Days 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine and bilirubin (direct/indirect and total). Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Clinical Chemistry Parameters of Alanine Transaminase (ALT), Alkaline Phosphatase (ALP) and Aspartate Transaminase (AST) [Days 1, 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; ALT, ALP and AST.
Change From Baseline in Clinical Chemistry Parameter: ALT, ALP and AST [Baseline (Day 1) and at Days 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; ALT, ALP and AST. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Absolute Values of Clinical Chemistry Parameters of Albumin [Days 1, 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; Albumin.
Change From Baseline in Clinical Chemistry Parameter: Albumin [Baseline (Day 1) and at Days 14, 28, 42 and 59]
Blood samples will be collected for the analysis of clinical chemistry parameters including; Albumin. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.
Participants who are Stage 3, 4 or 5 CKD defined by estimated Glomerular Filtration Rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
Hemoglobin as measured by HemoCue at screening visit and Day 1 is <=11.0 grams/deciliter (g/dL) [<=110 gram/Litre (g/L)].
Palpable brachial artery as assessed at screening.
Participants, if necessary may be on stable maintenance oral iron supplementation (<50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period). If participants have been on intravenous (IV) iron, then participants will not have received IV iron for 4 weeks prior to the Day 1 visit.
Male or female participants will be included.
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who has been on an approved form of contraceptive for the 4 weeks prior to Day 1 and agrees to follow the contraceptive guidance until the Follow-up visit.
Capable of giving signed informed consent.

Exclusion Criteria:

On dialysis or clinical evidence of impending need to initiate dialysis within 12 weeks of Day 1.
Planned kidney transplant within 12 weeks of Day 1.
Presence of an arteriovenous (AV) fistula.
Recombinant human erythropoietin use within the 12 weeks prior to the screening visit and through Day 1.
History of severe allergic or anaphylactic reactions or hypersensitivity to the study treatment or challenge agents, or excipients in the study treatments or challenge agents.
Planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until all assessments on Day 42 have been successfully completed.
The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or within 5 half-lives of the investigational product (whichever is longer) prior to screening and through Day 1.
At or below the lower limit of the reference range at screening for Vitamin B12 (may rescreen in a minimum of 8 weeks).
Ferritin <=50 nanograms/milliliter [<=50 microgram/liter (µg/L)] at screening.
Transferrin saturation (TSAT) <=15% (0.15) at screening.
Folate <2.0 nanogram/milliliter (4.5 nanomoles/liter; may rescreen in a minimum of 8 weeks) at screening.
High sensitivity C-reactive protein (hs-CRP) >=50 micrograms/milliliter (>=50 mg/L) at screening.
Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening and through Day 1.
Hospitalization for greater than 24 hours <=12 weeks prior to screening and through Day 1.
Stroke or transient ischemic attack <=12 weeks prior to screening and through Day 1.
Class 4 heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
Resting SBP >180 millimeters of mercury (mmHg) or DBP >110 mmHg at screening visit or current uncontrolled hypertension as determined by the investigator.
QT interval corrected for heart rate using Bazett's formula (QTcB) >500 milliseconds (msec), or QTcB >530 msec in participants with bundle branch block. There is no corrected QT (QTc) exclusion for participants with a predominantly ventricular paced rhythm.
Active chronic inflammatory disease that could impact erythropoiesis.
History of bone marrow aplasia or pure red cell aplasia.
Conditions, other than anemia of CKD, which can affect erythropoiesis.
Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding from <=8 weeks prior to screening and through Day 1.
ALT >2 times upper limit of normal (ULN; screening only).
Bilirubin >1.5 times ULN (screening only); Isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Major surgery within the 12 weeks prior to screening and through Day 1, or planned during the study.
Anticipated or planned vascular access surgery (i.e., arteriovenous [AV] fistula) within the 12 weeks prior to screening and through the Day 42 assessments.
Received a tissue heart valve replacement or repair within the 6 months prior to screening or has received a mechanical heart valve replacement.
Blood transfusion within 6 weeks prior to screening and through Day 1, or an anticipated need for blood transfusion during the study.
Clinical evidence of an acute infection, or history of infection requiring IV antibiotic therapy from 8 weeks prior to screening and through Day 1. Prophylactic oral antibiotics are allowed.
History of malignancy within the two years prior to screening and through Day 1 or currently receiving treatment for cancer, with the exception of localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.
Platelet count <50,000/µL (<50 Giga cells per liter).
History of a bleeding disorder (e.g., hemophilia).
Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Cambridge	Cambridgeshire	United Kingdom	CB2 0QQ
2	GSK Investigational Site	Edinburgh		United Kingdom	EH16 4TJ
3	GSK Investigational Site	London		United Kingdom	SE1 7EH

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT03446612

Other Study ID Numbers:

205767
2017-002268-42

First Posted:

Feb 27, 2018

Last Update Posted:

Dec 30, 2021

Last Verified:

Dec 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by GlaxoSmithKline

Additional relevant MeSH terms:

Kidney Diseases

Renal Insufficiency, Chronic

omega-N-Methylarginine

Study Results

Participant Flow

Recruitment Details	This was an open label, parallel group study that evaluated the effect of daprodustat and darbepoetin alfa on forearm blood flow (FBF) in participants with anemia of chronic kidney disease that are not dialysis dependent.
Pre-assignment Detail	Participants were enrolled in multiple centers in United Kingdom. A total of 6 participants were enrolled in the study and only 5 participants were randomized to receive study treatment.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Period Title: Overall Study
STARTED	2	3
COMPLETED	2	2
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Daprodustat	Darbepoetin Alfa	Total
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).	Total of all reporting groups
Overall Participants	2	3	5
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.0 (2.83)	53.0 (15.72)	56.6 (12.24)
Sex: Female, Male (Count of Participants)
Female	1 50%	1 33.3%	2 40%
Male	1 50%	2 66.7%	3 60%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian/European Heritage	2 100%	3 100%	5 100%

Outcome Measures

1. Primary Outcome

Title	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine (ACH) was infused intra-arterially at 7.5, 15 and 30 micrograms/minute (ug/min) each for 6 minutes per infusion. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
Pharmacodynamic Per-Protocol (PDPP) population included all randomized participants who provided pharmacodynamic (PD) data at Day 1 and Day 42. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	2
ACH 7.5 ug/min, n=2, 2	1.1304 (0.30030)	0.4351 (0.17032)
ACH 15 ug/min, n=1, 2	0.7866 (NA)	0.6183 (0.00435)
ACH 30 ug/min, n=1, 2	1.1328 (NA)	0.8090 (0.28395)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	0.6953
	Confidence Interval	() % to
	Parameter Dispersion	Type: Standard Deviation Value: 0.12998
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to acetylcholine (7.5 ug/min) is presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	0.1683
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to acetylcholine (15 ug/min) is presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	0.3238
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to acetylcholine (30 ug/min) is presented.

2. Secondary Outcome

Title	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to acetylcholine is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	2
7.5 ug/min, n=2, 2	8.3180 (4.50592)	-6.0360 (3.09976)
15 ug/min, n=1, 2	-4.6374 (NA)	-8.8299 (9.98143)
30 ug/min, n=1, 2	-2.6735 (NA)	-4.5121 (5.66731)

3. Secondary Outcome

Title	Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1	2
3 ug/min	1.0388 (NA)	0.7420 (0.07407)
10 ug/min	2.1447 (NA)	0.7022 (0.00860)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	0.2968
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to sodium nitroprusside (3 ug/min) is presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	1.4425
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to sodium nitroprusside (10 ug/min) is presented.

4. Secondary Outcome

Title	Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to sodium nitroprusside is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1	2
3 ug/min	-0.2560 (NA)	0.3844 (0.52197)
10 ug/min	6.8103 (NA)	-0.2873 (1.11519)

5. Secondary Outcome

Title	Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 micromoles per minute (umol/min) each infused for 6 minutes into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1	1
2 umol/min	0.7426 (NA)	0.9024 (NA)
8 umol/min	0.4975 (NA)	0.8690 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	-0.1598
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to L-NMMA (2 umol/min) is presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	FBF ratio difference
	Estimated Value	-0.3715
	Confidence Interval	() % to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between daprodustat and darbepoetin alfa FBF ratio in response to L-NMMA (8 umol/min) is presented.

6. Secondary Outcome

Title	Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to L-NMMA is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1	1
2 umol/min	1.1508 (NA)	0.3558 (NA)
8 umol/min	0.0974 (NA)	0.0399 (NA)

7. Secondary Outcome

Title	Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.
Measure Participants	2
7.5 ug/min, n=2	0.2744 (0.91996)
15 ug/min, n=1	-0.8503 (NA)
30 ug/min, n=1	0.5482 (NA)

8. Secondary Outcome

Title	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.
Measure Participants	1
3 ug/min	0.1618 (NA)
10 ug/min	3.2651 (NA)

9. Secondary Outcome

Title	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.
Measure Participants	1
2 umol/min	-0.3896 (NA)
8 umol/min	-0.7216 (NA)

10. Secondary Outcome

Title	Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2
7.5 ug/min	-2.0376 (0.63291)
15 ug/min	-1.4559 (0.01558)
30 ug/min	-1.0652 (1.56389)

11. Secondary Outcome

Title	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population.

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2
3 ug/min	-0.7503 (0.26692)
10 ug/min	-1.2405 (0.15366)

12. Secondary Outcome

Title	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1
2 umol/min	-0.081 (NA)
8 umol/min	-0.1351 (NA)

13. Secondary Outcome

Title	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with daprodustat.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days
Measure Participants	2
7.5 ug/min, n=2	8.3180 (4.50592)
15 ug/min, n=1	-4.6374 (NA)
30 ug/min, n=1	-2.6735 (NA)

14. Secondary Outcome

Title	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with daprodustat.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days
Measure Participants	1
3 ug/min	-0.2560 (NA)
10 ug/min	6.8103 (NA)

15. Secondary Outcome

Title	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with daprodustat.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days
Measure Participants	1
2 umol/min	1.1508 (NA)
8 umol/min	0.0974 (NA)

16. Secondary Outcome

Title	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with darbepoetin alfa.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2
7.5 ug/min	-6.0360 (3.09976)
15 ug/min	-8.8299 (9.98143)
30 ug/min	-4.5121 (5.66731)

17. Secondary Outcome

Title	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with darbepoetin alfa.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2
3 ug/min	0.3844 (0.52197)
10 ug/min	-0.2873 (1.11519)

18. Secondary Outcome

Title	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa
Description	Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with darbepoetin alfa.
Time Frame	Day 1 and Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	1
2 umol/min	0.3558 (NA)
8 umol/min	0.0399 (NA)

19. Secondary Outcome

Title	Change in Augmentation Index (AIx) From Day 1 to 42
Description	Pulse wave analysis (PWA) is a reproducible, noninvasive method for assessing AIx (a measure of the contribution that wave reflection makes to the arterial pressure waveform). The amplitude and timing of the reflected wave ultimately depends on the stiffness of the small (pre-resistance) vessels and large arteries, and thus, AIx provides a measure of systemic arterial stiffness. A high-fidelity micro manometer was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the radial artery of the dominant arm using gentle pressure. AIx was defined as the augmentation (difference between systolic peaks) expressed as a percentage of the overall pulse pressure. Data for change in AIx from Day 1 to 42 was presented.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	2
Mean (Standard Deviation) [Percentage]	-3.000 (0.0000)	-4.000 (2.8284)

20. Secondary Outcome

Title	Change in Pulse Wave Velocity (PWV) From Day 1 to Day 42
Description	PWV was assessed with a high-fidelity micro manometer which was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the carotid and femoral arteries as the two points of measure. Data for change in PWV from Day 1 to 42 was presented.
Time Frame	Day 1 to Day 42

Outcome Measure Data

Analysis Population Description
PDPP Population

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	2
Mean (Standard Deviation) [meters per second (m/sec)]	2.075 (1.4496)	0.100 (0.2828)

21. Secondary Outcome

Title	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE is any untoward medical occurrence in a clinical study participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/birth effect.
Time Frame	Up to 59 days

Outcome Measure Data

Analysis Population Description
Safety Population includes all randomised participants who received at least one dose of study treatment.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Any AEs	0 0%	1 33.3%
Any SAEs	0 0%	0 0%

22. Secondary Outcome

Title	Number of Participants With Any AE of Special Interest (AESI)
Description	AESIs were identified based on non-clinical studies with daprodustat, clinical experience with recombinant human erythropoietins (rhEPOs), and current information regarding hypoxia-inducible factor (HIF)-regulated pathways in mediating hypoxia-associated pathophysiology. The AESIs for daprodustat were identified as follows: Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis; Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular access; Cardiomyopathy; Pulmonary artery hypertension; Cancer-related mortality and tumor progression and recurrence Esophageal and gastric erosions; Proliferative retinopathy, macular edema, choroidal neovascularization; Exacerbation of rheumatoid arthritis and Worsening of hypertension.
Time Frame	Up to 59 days

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Count of Participants [Participants]	0 0%	0 0%

23. Secondary Outcome

Title	Number of Participants Discontinuing the Randomized Study Treatment
Description	Number of participants who discontinued the randomized study treatment were assessed.
Time Frame	Up to Day 42

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Count of Participants [Participants]	0 0%	0 0%

24. Other Pre-specified Outcome

Title	Absolute Values of Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Description	DBP and SBP were measured in a semi-supine position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Time Frame	Days 1, 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
DBP, Day 1, n=2, 3	73.5 (13.44)	69.3 (13.05)
DBP, Day 14, n=2, 3	67.0 (5.66)	74.3 (13.05)
DBP, Day 28, n=2, 3	73.5 (7.78)	79.3 (25.54)
DBP, Day 42, n=2, 2	76.0 (9.90)	73.0 (8.49)
DBP, Day 59, n=2, 3	69.5 (9.19)	82.7 (18.15)
SBP, Day 1, n=2, 3	144.0 (43.84)	134.3 (18.34)
SBP, Day 14, n=2, 3	130.0 (28.28)	127.7 (23.25)
SBP, Day 28, n=2, 3	135.5 (12.02)	147.3 (39.63)
SBP, Day 42, n=2, 2	145.5 (33.23)	148.0 (45.25)
SBP, Day 59, n=2, 3	135.5 (31.82)	142.3 (29.14)

25. Other Pre-specified Outcome

Title	Change From Baseline in DBP and SBP
Description	DBP and SBP were measured in a semi-supine position with a completely automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
DBP, Day 14, n=2, 3	-6.5 (7.78)	5.0 (0.00)
DBP, Day 28, n=2, 3	0.0 (21.21)	10.0 (13.00)
DBP, Day 42, n=2, 2	2.5 (3.54)	10.5 (0.71)
DBP, Day 59, n=2, 3	-4.0 (4.24)	13.3 (5.13)
SBP, Day 14, n=2, 3	-14.0 (15.56)	-6.7 (4.93)
SBP, Day 28, n=2, 3	-8.5 (31.82)	13.0 (38.43)
SBP, Day 42, n=2, 2	1.5 (10.61)	10.5 (20.51)
SBP, Day 59, n=2, 3	-8.5 (12.02)	8.0 (24.02)

26. Other Pre-specified Outcome

Title	Absolute Values of Electrocardiogram (ECG) Mean Heart Rate
Description	Full 12-lead ECG were recorded with the participant in a semi-supine position to measure heart rate.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	69.0 (2.83)	70.0 (14.11)
Day 42, n=2, 2	61.0 (14.14)	62.0 (9.90)
Day 59, n=2, 3	71.5 (9.19)	73.7 (20.03)

27. Other Pre-specified Outcome

Title	Change From Baseline in ECG Mean Heart Rate
Description	Full 12-lead ECG were recorded with the participant in a semi-supine position to measure heart rate. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 42, n=2, 2	-8.0 (11.31)	-0.5 (2.12)
Day 59, n=2, 3	2.5 (12.02)	3.7 (9.50)

28. Other Pre-specified Outcome

Title	Absolute Values of ECG Parameters- PR Interval, QRS Interval, and QT Interval and QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB)
Description	Full 12-lead ECGs were recorded with the participant in a semi-supine position to measure PR interval, QRS duration, QT interval and QTcB, calculated (machine read or manually).
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
PR Interval, Day 1, n=2, 3	139.0 (1.41)	181.7 (23.16)
PR Interval, Day 42, n=2, 2	146.5 (7.78)	192.5 (10.61)
PR Interval, Day 59, n=2, 3	146.5 (2.12)	182.0 (18.00)
QRS Duration, Day 1, n=2, 3	87.0 (7.07)	94.7 (5.03)
QRS Duration, Day 42, n=2, 2	88.5 (9.19)	96.5 (10.61)
QRS Duration, Day 59, n=2, 3	87.0 (9.90)	95.3 (7.02)
QT Interval, Day 1, n=2, 3	395.5 (6.36)	391.3 (14.47)
QT Interval, Day 42, n=2, 2	413.5 (20.51)	388.0 (11.31)
QT Interval, Day 59, n=2, 3	383.5 (44.55)	382.3 (33.71)
QTcB Interval, Day 1, n=2, 3	424.0 (1.41)	420.7 (31.79)
QTcB Interval, Day 42, n=2, 2	414.5 (27.58)	393.0 (19.80)
QTcB Interval, Day 59, n=2, 3	416.5 (21.92)	417.3 (33.32)

29. Other Pre-specified Outcome

Title	Change From Baseline in ECG Parameters- PR Interval, QRS Duration, and QT Interval and QTcB
Description	Full 12-lead ECGs were recorded with the participant in a semi-supine position to measure PR interval, QRS duration, QT (uncorrected) interval and QTcB, calculated (machine read or manually). Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
PR Interval, Day 42, n=2, 2	7.5 (6.36)	-2.0 (19.80)
PR Interval, Day 59, n=2, 3	7.5 (0.71)	0.3 (16.86)
QRS Duration, Day 42, n=2, 2	1.5 (2.12)	1.5 (3.54)
QRS Duration, Day 59, n=2, 3	0.0 (2.83)	0.7 (2.31)
QT Interval, Day 42, n=2, 2	18.0 (14.14)	-7.0 (7.07)
QT Interval, Day 59, n=2, 3	-12.0 (50.91)	-9.0 (19.67)
QTcB Interval, Day 42, n=2, 2	-9.5 (26.16)	-9.5 (13.44)
QTcB Interval, Day 59, n=2, 3	-7.5 (20.51)	-3.3 (8.02)

30. Other Pre-specified Outcome

Title	Absolute Values of the Hematology Parameters of Platelet Count, White Blood Cell (WBC) Count (Absolute), Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils
Description	Blood samples were collected for the analysis of hematology parameters including platelet count, leukocytes, basophils, eosinophils, lymphocytes, monocytes and neutrophils.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Platelet count, Day 1, n=2, 3	199.0 (63.64)	191.7 (68.13)
Platelet count, Day 42, n=2, 2	203.5 (57.28)	121.5 (13.44)
Platelet count, Day 59, n=2, 3	193.0 (41.01)	50.08 (50.08)
Leukocytes, Day 1, n=2, 3	5.05 (1.202)	6.30 (2.117)
Leukocytes, Day 42, n=2, 2	6.05 (2.616)	5.75 (2.051)
Leukocytes, Day 59, n=2, 3	5.30 (1.414)	7.20 (2.261)
Basophils, Day 1, n=2, 3	0.045 (0.0212)	0.057 (0.0503)
Basophils, Day 42, n=2, 2	0.045 (0.0212)	0.045 (0.0212)
Basophils, Day 59, n=2, 3	0.035 (0.0071)	0.050 (0.0400)
Eosinophils, Day 1, n=2, 3	0.295 (0.1485)	0.230 (0.1353)
Eosinophils, Day 42, n=2, 2	0.300 (0.1980)	0.175 (0.0778)
Eosinophils, Day 59, n=2, 3	0.245 (0.1485)	0.220 (0.1311)
Lymphocytes, Day 1, n=2, 3	1.160 (0.2404)	2.037 (1.4989)
Lymphocytes, Day 42, n=2, 2	1.275 (0.2616)	1.150 (0.4808)
Lymphocytes, Day 59, n=2, 3	0.785 (0.3748)	2.033 (1.3580)
Monocytes, Day 1, n=2, 3	0.400 (0.0566)	0.607 (0.3147)
Monocytes, Day 42, n=2, 2	0.415 (0.0071)	0.445 (0.2192)
Monocytes, Day 59, n=2, 3	0.415 (0.0778)	0.563 (0.2574)
Neutrophils, Day 1, n=2, 3	3.160 (1.3576)	3.387 (0.2053)
Neutrophils, Day 42, n=2, 2	4.010 (2.6870)	3.970 (2.1920)
Neutrophils, Day 59, n=2, 3	3.825 (1.0112)	4.343 (1.0060)

31. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameters of Platelet Count, Leukocytes, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils
Description	Blood samples were collected for the analysis of hematology parameters including platelet count, WBC count (Absolute), basophils, eosinophils, lymphocytes, monocytes and neutrophils. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Platelet count, Day 42, n=2, 2	4.5 (6.36)	-51.0 (70.71)
Platelet count, Day 59, n=2, 3	-6.0 (22.63)	-26.3 (51.98)
Leukocytes, Day 42, n=2, 2	1.00 (1.414)	0.65 (2.616)
Leukocytes, Day 59, n=2, 3	0.25 (0.212)	0.90 (1.054)
Basophils, Day 42, n=2, 2	0.000 (0.0000)	0.015 (0.0071)
Basophils, Day 59, n=2, 3	-0.010 (0.0283)	-0.007 (0.0115)
Eosinophils, Day 42, n=2, 2	0.005 (0.0495)	0.015 (0.0071)
Eosinophils, Day 59, n=2, 3	-0.050 (0.0000)	-0.010 (0.0100)
Lymphocytes, Day 42, n=2, 2	0.115 (0.0212)	-0.040 (0.0424)
Lymphocytes, Day 59, n=2, 3	-0.375 (0.6152)	-0.003 (0.1443)
Monocytes, Day 42, n=2, 2	0.015 (0.0636)	0.020 (0.2263)
Monocytes, Day 59, n=2, 3	0.015 (0.0212)	-0.043 (0.0586)
Neutrophils, Day 42, n=2, 2	0.850 (1.3294)	0.670 (2.3900)
Neutrophils, Day 59, n=2, 3	0.665 (0.3465)	0.957 (1.0929)

32. Other Pre-specified Outcome

Title	Absolute Values of the Hematology Parameter of Red Blood Cell (RBC) Count and Reticulocyte Count (RC)
Description	Blood samples were collected for the analysis of hematology parameters including RBC count and RC.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
RBC, Day 1, n=2, 3	3.45 (0.354)	3.20 (0.300)
RBC, Day 42, n=2, 2	3.30 (0.283)	3.65 (0.071)
RBC, Day 59, n=2, 3	3.35 (0.354)	3.63 (0.493)
RC, Day 1, n=2, 3	0.04090 (0.018102)	0.06090 (0.038112)
RC, Day 42, n=2, 2	0.04610 (0.023052)	0.07970 (0.057983)
RC, Day 59, n=2, 3	0.03490 (0.014708)	0.04580 (0.049537)

33. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameters of RBC Count and RC
Description	Blood samples were collected for the analysis of hematology parameters including RBC count and RC. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
RBC, Day 42, n=2, 2	-0.15 (0.071)	0.60 (0.141)
RBC, Day 59, n=2, 3	-0.10 (0.000)	0.43 (0.252)
RC, Day 42, n=2, 2	0.00520 (0.004950)	0.00815 (0.010819)
RC, Day 59, n=2, 3	-0.00600 (0.003394)	-0.01510 (0.011467)

34. Other Pre-specified Outcome

Title	Absolute Values of the Hematology Parameters of Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC)
Description	Blood samples were collected for the analysis of hematology parameters including hemoglobin and MCHC.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Hemoglobin, Day 1, n=2, 3	10.60 (0.849)	9.77 (0.586)
Hemoglobin, Day 42, n=2, 2	10.45 (0.778)	11.40 (0.424)
Hemoglobin, Day 59, n=2, 3	10.40 (0.849)	11.27 (1.002)
MCHC, Day 1, n=2, 3	34.10 (0.000)	34.23 (0.351)
MCHC, Day 42, n=2, 2	34.10 (0.141)	33.75 (1.909)
MCHC, Day 59, n=2, 3	34.00 (0.141)	34.33 (1.447)

35. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameters- Hemoglobin and MCHC
Description	Blood samples were collected for the analysis of hematology parameters including hemoglobin and MCHC. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Hemoglobin, Day 42, n=2, 2	-0.15 (0.071)	1.85 (0.212)
Hemoglobin, Day 59, n=2, 3	-0.20 (0.000)	1.50 (0.520)
MCHC, Day 42, n=2, 2	0.00 (0.141)	-0.65 (1.626)
MCHC, Day 59, n=2, 3	-0.10 (0.141)	0.10 (1.127)

36. Other Pre-specified Outcome

Title	Absolute Values of Hematology Parameter: Hematocrit
Description	Blood samples were collected for the analysis of hematology parameters including hematocrit.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	0.3105 (0.02616)	0.2850 (0.01769)
Day 42, n=2, 2	0.3065 (0.02475)	0.3385 (0.00636)
Day 59, n=2, 3	0.3065 (0.02475)	0.3277 (0.03412)

37. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameter: Hematocrit
Description	Blood samples were collected for the analysis of hematology parameters including hematocrit. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 42, n=2, 2	-0.0040 (0.00141)	0.0615 (0.02192)
Day 59, n=2, 3	-0.0040 (0.00141)	0.0427 (0.02212)

38. Other Pre-specified Outcome

Title	Absolute Values of Hematology Parameter of Red Blood Cell Distribution Width (RDW)
Description	Blood samples were collected for the analysis of hematology parameters including RDW.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	0.3105 (0.02616)	0.2850 (0.01769)
Day 42, n=2, 2	13.45 (0.212)	14.00 (0.424)
Day 59, n=2, 3	13.20 (0.141)	13.70 (0.200)

39. Other Pre-specified Outcome

Title	Change From Baseline in RDW
Description	Blood samples were collected for the analysis of hematology parameters including RDW. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 42, n=2, 2	0.00 (0.424)	1.15 (0.636)
Day 59, n=2, 3	-0.25 (0.354)	0.70 (0.436)

40. Other Pre-specified Outcome

Title	Absolute Values of the Hematology Parameter of Mean Corpuscular Hemoglobin (MCH)
Description	Blood samples were collected for the analysis of hematology parameters including MCH.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	30.95 (0.354)	30.67 (1.457)
Day 42, n=2, 2	31.40 (0.424)	31.40 (0.707)
Day 59, n=2, 3	31.10 (0.141)	30.93 (1.716)

41. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameter of MCH
Description	Blood samples were collected for the analysis of hematology parameters including MCH. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 42, n=2, 2	0.45 (0.071)	-0.10 (0.990)
Day 59, n=2, 3	0.15 (0.212)	0.27 (0.862)

42. Other Pre-specified Outcome

Title	Absolute Values of the Hematology Parameter of Mean Corpuscular Volume (MCV)
Description	Blood samples were collected for the analysis of hematology parameters including MCV.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	91.0 (1.41)	89.7 (3.51)
Day 42, n=2, 2	92.0 (1.41)	93.0 (2.83)
Day 59, n=2, 3	91.5 (0.71)	90.0 (3.00)

43. Other Pre-specified Outcome

Title	Change From Baseline in Hematology Parameter of MCV
Description	Blood samples were collected for the analysis of hematology parameters including MCV. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 42, n=2, 2	1.0 (0.00)	1.5 (0.71)
Day 59, n=2, 3	0.5 (0.71)	0.3 (0.58)

44. Other Pre-specified Outcome

Title	Absolute Values of Clinical Chemistry Parameters of Sodium, Potassium, Carbon-dioxide (Total), Chloride, Glucose and Urea
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; sodium, potassium, carbon-dioxide (total), chloride, glucose and urea.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Sodium, Day 1, n=2, 3	140.0 (1.41)	136.7 (0.58)
Sodium, Day 42, n=2, 2	139.5 (3.54)	135.0 (7.07)
Sodium, Day 59, n=2, 3	138.5 (0.71)	136.0 (2.65)
Potassium, Day 1, n=2, 3	4.70 (0.141)	5.03 (0.757)
Potassium, Day 42, n=2, 2	4.55 (0.495)	5.15 (0.495)
Potassium, Day 59, n=2, 3	4.45 (0.071)	4.77 (0.306)
Carbon-dioxide (total), Day 1, n=2, 3	20.5 (3.54)	19.0 (3.46)
Carbon-dioxide (total), Day 42, n=2, 2	22.0 (1.41)	19.0 (0.00)
Carbon-dioxide (total), Day 59, n=2, 3	22.5 (2.12)	21.0 (2.00)
Chloride, Day 1, n=2, 3	108.0 (0.00)	105.7 (5.03)
Chloride, Day 42, n=2, 2	108.0 (4.24)	104.0 (9.90)
Chloride, Day 59, n=2, 3	108.0 (2.83)	104.7 (3.51)
Glucose, Day 1, n=2, 3	7.60 (3.111)	6.40 (4.424)
Glucose, Day 42, n=2, 2	6.95 (2.333)	12.50 (12.162)
Glucose, Day 59, n=2, 3	7.45 (4.172)	10.10 (7.066)
Urea, Day 1, n=2, 3	18.00 (2.828)	16.67 (5.508)
Urea, Day 42, n=2, 2	16.75 (2.475)	21.00 (0.707)
Urea, Day 59, n=2, 3	16.50 (0.707)	19.33 (5.795)

45. Other Pre-specified Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: Sodium, Potassium, Carbon-dioxide (Total), Chloride, Glucose and Urea
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; sodium, potassium, carbon-dioxide (total), chloride, glucose and urea. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Sodium, Day 42, n=2, 2	-0.5 (4.95)	-1.5 (6.36)
Sodium, Day 59, n=2, 3	-1.5 (2.12)	-0.7 (2.31)
Potassium, Day 42, n=2, 2	-0.15 (0.354)	-0.05 (0.495)
Potassium, Day 59, n=2, 3	-0.25 (0.071)	-0.27 (0.503)
Carbon-dioxide (total), Day 42, n=2, 2	1.5 (4.95)	1.0 (4.24)
Carbon-dioxide (total), Day 59, n=2, 3	2.0 (1.41)	2.0 (2.00)
Chloride, Day 42, n=2, 2	0.0 (4.24)	-2.0 (2.83)
Chloride, Day 59, n=2, 3	0.0 (2.83)	1.73 (1.73)
Glucose, Day 42, n=2, 2	-0.65 (0.778)	4.25 (7.849)
Glucose, Day 59, n=2, 3	-0.15 (1.061)	3.70 (3.477)
Urea, Day 42, n=2, 2	-1.25 (5.303)	3.00 (7.778)
Urea, Day 59, n=2, 3	-1.50 (3.536)	2.67 (2.754)

46. Other Pre-specified Outcome

Title	Absolute Values of Clinical Chemistry Parameters of Creatinine
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine.
Time Frame	Days 1, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Creatinine, Day 1, n=2, 3	246.65 (9.970)	225.40 (74.164)
Creatinine, Day 42, n=2, 2	249.75 (15.627)	272.25 (88.742)
Creatinine, Day 59, n=2, 3	260.35 (8.132)	245.17 (91.086)

47. Other Pre-specified Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: Creatinine
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Creatinine, Day 42, n=2, 2	3.10 (5.657)	36.70 (13.152)
Creatinine, Day 59, n=2, 3	13.70 (18.102)	19.77 (33.416)

48. Other Pre-specified Outcome

Title	Absolute Values of Clinical Chemistry Parameters of Bilirubin (Direct/Indirect and Total)
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; bilirubin (direct/indirect and total).
Time Frame	Days 1, 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Bilirubin total, Day 1, n=2, 3	5.0 (1.41)	6.0 (0.00)
Bilirubin total, Day 14, n=2, 3	5.0 (1.41)	7.3 (1.15)
Bilirubin total, Day 28, n=2, 3	6.0 (0.00)	6.0 (0.00)
Bilirubin total, Day 42, n=2, 2	6.0 (0.00)	9.0 (4.24)
Bilirubin total, Day 59, n=2, 3	5.0 (1.41)	6.7 (1.15)
Direct Bilirubin, Day 1, n=2, 2	1.0 (1.41)	2.0 (0.00)
Direct Bilirubin, Day 14, n=2, 2	1.0 (1.41)	2.0 (0.00)
Direct Bilirubin, Day 28, n=2, 2	1.0 (1.41)	2.0 (0.00)
Direct Bilirubin, Day 42, n=2, 1	2.0 (0.00)	2.0 (NA)
Direct Bilirubin, Day 59, n=2, 2	2.0 (0.00)	2.0 (0.00)
Indirect Bilirubin, Day 1, n=2, 2	4.0 (0.00)	4.0 (0.00)
Indirect Bilirubin, Day 14, n=2, 2	4.0 (0.00)	5.0 (1.41)
Indirect Bilirubin, Day 28, n=2, 2	5.0 (1.41)	4.0 (0.00)
Indirect Bilirubin, Day 42, n=2, 1	4.0 (0.00)	10.0 (NA)
Indirect Bilirubin, Day 59, n=2, 2	3.0 (1.41)	5.0 (1.41)

49. Other Pre-specified Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: Bilirubin (Direct/Indirect and Total)
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; creatinine and bilirubin (direct/indirect and total). Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Bilirubin total, Day 14, n=2, 3	0.0 (0.00)	1.3 (1.15)
Bilirubin total, Day 28, n=2, 3	1.0 (1.41)	0.0 (0.00)
Bilirubin total, Day 42, n=2, 2	1.0 (1.41)	3.0 (4.24)
Bilirubin total, Day 59, n=2, 3	0.0 (0.00)	0.7 (1.15)
Direct Bilirubin, Day 14, n=2, 2	0.0 (0.00)	0.0 (0.00)
Direct Bilirubin, Day 28, n=2, 2	0.0 (0.00)	0.0 (0.00)
Direct Bilirubin, Day 42, n=2, 1	1.0 (1.41)	0.0 (NA)
Direct Bilirubin, Day 59, n=2, 2	1.0 (1.41)	0.0 (0.00)
Indirect Bilirubin, Day 14, n=2, 2	0.0 (0.00)	1.0 (1.41)
Indirect Bilirubin, Day 28, n=2, 2	1.0 (1.41)	0.0 (0.00)
Indirect Bilirubin, Day 42, n=2, 1	0.0 (0.00)	6.0 (NA)
Indirect Bilirubin, Day 59, n=2, 2	-1.0 (1.41)	1.0 (1.41)

50. Other Pre-specified Outcome

Title	Absolute Values of Clinical Chemistry Parameters of Alanine Transaminase (ALT), Alkaline Phosphatase (ALP) and Aspartate Transaminase (AST)
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; ALT, ALP and AST.
Time Frame	Days 1, 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
ALT, Day 1, n=2, 3	21.0 (4.24)	26.7 (7.02)
ALT, Day 14, n=2, 3	15.0 (4.24)	20.3 (6.81)
ALT, Day 28, n=2, 3	15.5 (4.95)	18.3 (8.08)
ALT, Day 42, n=2, 2	16.0 (4.24)	22.0 (9.90)
ALT, Day 59, n=2, 3	20.5 (10.61)	23.3 (8.08)
ALP, Day 1, n=2, 3	113.5 (61.52)	95.0 (42.44)
ALP, Day 14, n=2, 3	97.0 (42.43)	91.0 (33.87)
ALP, Day 28, n=2, 3	99.5 (45.96)	91.7 (38.40)
ALP, Day 42, n=2, 2	99.0 (39.60)	100.5 (37.48)
ALP, Day 59, n=2, 3	108.5 (55.86)	90.3 (29.26)
AST, Day 1, n=2, 3	19.5 (7.78)	21.7 (1.53)
AST, Day 14, n=2, 3	16.5 (7.78)	18.3 (3.51)
AST, Day 28, n=2, 3	18.0 (9.90)	18.7 (7.09)
AST, Day 42, n=2, 2	17.5 (10.61)	16.5 (4.95)
AST, Day 59, n=2, 3	20.5 (10.61)	19.3 (6.03)

51. Other Pre-specified Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: ALT, ALP and AST
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; ALT, ALP and AST. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
ALT, Day 14, n=2, 3	-6.0 (0.00)	-6.3 (1.53)
ALT, Day 28, n=2, 3	-5.5 (0.71)	-8.3 (1.15)
ALT, Day 42, n=2, 2	-5.0 (0.00)	-5.0 (0.00)
ALT, Day 59, n=2, 3	-0.5 (6.36)	-3.3 (4.62)
ALP, Day 14, n=2, 3	-16.5 (19.09)	-4.0 (12.12)
ALP, Day 28, n=2, 3	-14.0 (15.56)	-3.3 (4.04)
ALP, Day 42, n=2, 2	-14.5 (21.92)	-6.5 (14.85)
ALP, Day 59, n=2, 3	-5.0 (5.66)	-4.7 (13.61)
AST, Day 14, n=2, 3	-3.0 (0.00)	-3.3 (2.08)
AST, Day 28, n=2, 3	-1.5 (2.12)	-3.0 (6.00)
AST, Day 42, n=2, 2	-2.0 (2.83)	-5.0 (2.83)
AST, Day 59, n=2, 3	1.0 (2.83)	-2.3 (5.03)

52. Other Pre-specified Outcome

Title	Absolute Values of Clinical Chemistry Parameters of Albumin
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; Albumin.
Time Frame	Days 1, 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 1, n=2, 3	37.0 (5.66)	41.7 (2.31)
Day 14, n=2, 3	36.5 (2.12)	40.7 (3.06)
Day 28, n=2, 3	35.5 (3.54)	39.3 (3.21)
Day 42, n=2, 2	35.5 (3.54)	38.5 (0.71)
Day 59, n=2, 3	36.5 (6.36)	40.3 (1.53)

53. Other Pre-specified Outcome

Title	Change From Baseline in Clinical Chemistry Parameter: Albumin
Description	Blood samples will be collected for the analysis of clinical chemistry parameters including; Albumin. Baseline value (Day 1) is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 14, 28, 42 and 59

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
Measure Participants	2	3
Day 14, n=2, 3	-0.05 (0.354)	-0.10 (0.200)
Day 28, n=2, 3	-0.15 (0.212)	-0.23 (0.321)
Day 42, n=2, 2	-0.15 (0.212)	-0.25 (0.354)
Day 59, n=2, 3	-0.05 (0.071)	-0.13 (0.153)

Adverse Events

	Daprodustat		Darbepoetin Alfa
Time Frame	Non-SAEs and SAEs were collected from the start of the treatment and Up to 59 days
Adverse Event Reporting Description	Non-SAEs and SAEs were collected in the Safety Population which comprised of participants who received at least one dose of study treatment.

Arm/Group Title	Daprodustat		Darbepoetin Alfa
Arm/Group Description	Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.		Participants were randomized to receive darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/3 (0%)
Serious Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		1/3 (33.3%)
Gastrointestinal disorders
Faeces soft	0/2 (0%)	0	1/3 (33.3%)	1
Abdominal pain upper	0/2 (0%)	0	1/3 (33.3%)	1
Metabolism and nutrition disorders
Gout	0/2 (0%)	0	1/3 (33.3%)	1
Bilateral foot discomfort secondary to Gout	0/2 (0%)	0	1/3 (33.3%)	1
Swollen right foot secondary to Gout	0/2 (0%)	0	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)	0	1/3 (33.3%)	1
Joint swelling	0/2 (0%)	0	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email	GSKClinicalSupportHD@gsk.com

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT03446612

Other Study ID Numbers:

205767
2017-002268-42

First Posted:

Feb 27, 2018

Last Update Posted:

Dec 30, 2021

Last Verified:

Dec 1, 2021