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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03446612

Enrollment

Registered

2018-02-27

Start date

2019-01-10

Completion date

2019-05-29

Last updated

2024-03-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anaemia

Keywords

darbepoetin alpha, challenge agents, daprodustat, FBF-CKD

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.

Interventions

DRUGL-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.

DRUGSodium 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.

DRUGDaprodustat

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.

DRUGDarbepoetin alfa

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

DRUGAcetylcholine

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

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.

Intervention model description

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

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 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.
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.

Other

Measure	Time frame	Description
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 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 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.
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 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.

Countries

United Kingdom

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 details

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.

Participants by arm

Arm	Count
Daprodustat Participants were randomized to receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.	2
Darbepoetin Alfa 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).	3
Total	5

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Protocol defined stopping criteria	0	1

Baseline characteristics

Characteristic	Daprodustat	Darbepoetin Alfa	Total
Age, Continuous	62.0 Years STANDARD_DEVIATION 2.83	53.0 Years STANDARD_DEVIATION 15.72	56.6 Years STANDARD_DEVIATION 12.24
Race/Ethnicity, Customized White/Caucasian/European Heritage	2 Participants	3 Participants	5 Participants
Sex: Female, Male Female	1 Participants	1 Participants	2 Participants
Sex: Female, Male Male	1 Participants	2 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 2	0 / 3
other Total, other adverse events	0 / 2	1 / 3
serious Total, serious adverse events	0 / 2	0 / 3

Outcome results

Primary

Change in FBF Ratio in Response to Acetylcholine (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.

Time frame: Day 1 to Day 42

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 7.5 ug/min, n=2, 2	1.1304 Ratio	Standard Deviation 0.3003
Daprodustat	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 15 ug/min, n=1, 2	0.7866 Ratio	—
Daprodustat	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 30 ug/min, n=1, 2	1.1328 Ratio	—
Darbepoetin Alfa	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 7.5 ug/min, n=2, 2	0.4351 Ratio	Standard Deviation 0.17032
Darbepoetin Alfa	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 15 ug/min, n=1, 2	0.6183 Ratio	Standard Deviation 0.00435
Darbepoetin Alfa	Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)	ACH 30 ug/min, n=1, 2	0.8090 Ratio	Standard Deviation 0.28395

Secondary

Change in Augmentation Index (AIx) From Day 1 to 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.

Time frame: Day 1 to Day 42

Population: PDPP Population

Arm	Measure	Value (MEAN)	Dispersion
Daprodustat	Change in Augmentation Index (AIx) From Day 1 to 42	-3.000 Percentage	Standard Deviation 0
Darbepoetin Alfa	Change in Augmentation Index (AIx) From Day 1 to 42	-4.000 Percentage	Standard Deviation 2.8284

Secondary

Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat	7.5 ug/min, n=2	0.2744 Ratio	Standard Deviation 0.91996
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat	15 ug/min, n=1	-0.8503 Ratio	—
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat	30 ug/min, n=1	0.5482 Ratio	—

Secondary

Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

Time frame: Day 1 and Day 42

Population: PDPP Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	7.5 ug/min	-2.0376 Ratio	Standard Deviation 0.63291
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	15 ug/min	-1.4559 Ratio	Standard Deviation 0.01558
Daprodustat	Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	30 ug/min	-1.0652 Ratio	Standard Deviation 1.56389

Secondary

Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat	2 umol/min	-0.3896 Ratio
Daprodustat	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat	8 umol/min	-0.7216 Ratio

Secondary

Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

Time frame: Day 1 and Day 42

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	2 umol/min	-0.081 Ratio
Daprodustat	Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	8 umol/min	-0.1351 Ratio

Secondary

Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (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 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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)	2 umol/min	0.7426 Ratio
Daprodustat	Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)	8 umol/min	0.4975 Ratio
Darbepoetin Alfa	Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)	2 umol/min	0.9024 Ratio
Darbepoetin Alfa	Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)	8 umol/min	0.8690 Ratio

Secondary

Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat	3 ug/min	0.1618 Ratio
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat	10 ug/min	3.2651 Ratio

Secondary

Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

Time frame: Day 1 and Day 42

Population: PDPP Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	3 ug/min	-0.7503 Ratio	Standard Deviation 0.26692
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	10 ug/min	-1.2405 Ratio	Standard Deviation 0.15366

Secondary

Change in FBF Ratio 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. 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

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)	3 ug/min	1.0388 Ratio	—
Daprodustat	Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)	10 ug/min	2.1447 Ratio	—
Darbepoetin Alfa	Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)	3 ug/min	0.7420 Ratio	Standard Deviation 0.07407
Darbepoetin Alfa	Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)	10 ug/min	0.7022 Ratio	Standard Deviation 0.0086

Secondary

Change in Pulse Wave Velocity (PWV) From 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.

Time frame: Day 1 to Day 42

Population: PDPP Population

Arm	Measure	Value (MEAN)	Dispersion
Daprodustat	Change in Pulse Wave Velocity (PWV) From Day 1 to Day 42	2.075 meters per second (m/sec)	Standard Deviation 1.4496
Darbepoetin Alfa	Change in Pulse Wave Velocity (PWV) From Day 1 to Day 42	0.100 meters per second (m/sec)	Standard Deviation 0.2828

Secondary

Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine

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

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	7.5 ug/min, n=2, 2	8.3180 ug/min	Standard Deviation 4.50592
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	15 ug/min, n=1, 2	-4.6374 ug/min	—
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	30 ug/min, n=1, 2	-2.6735 ug/min	—
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	7.5 ug/min, n=2, 2	-6.0360 ug/min	Standard Deviation 3.09976
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	15 ug/min, n=1, 2	-8.8299 ug/min	Standard Deviation 9.98143
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine	30 ug/min, n=1, 2	-4.5121 ug/min	Standard Deviation 5.66731

Secondary

Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA	2 umol/min	1.1508 umol/min
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA	8 umol/min	0.0974 umol/min
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA	2 umol/min	0.3558 umol/min
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA	8 umol/min	0.0399 umol/min

Secondary

Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside

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

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside	3 ug/min	-0.2560 ug/min	—
Daprodustat	Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside	10 ug/min	6.8103 ug/min	—
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside	3 ug/min	0.3844 ug/min	Standard Deviation 0.52197
Darbepoetin Alfa	Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside	10 ug/min	-0.2873 ug/min	Standard Deviation 1.11519

Secondary

Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat	7.5 ug/min, n=2	8.3180 ug/min	Standard Deviation 4.50592
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat	15 ug/min, n=1	-4.6374 ug/min	—
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat	30 ug/min, n=1	-2.6735 ug/min	—

Secondary

Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

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

Population: PDPP Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	7.5 ug/min	-6.0360 ug/min	Standard Deviation 3.09976
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	15 ug/min	-8.8299 ug/min	Standard Deviation 9.98143
Daprodustat	Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	30 ug/min	-4.5121 ug/min	Standard Deviation 5.66731

Secondary

Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat	2 umol/min	1.1508 umol/min
Daprodustat	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat	8 umol/min	0.0974 umol/min

Secondary

Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	2 umol/min	0.3558 umol/min
Daprodustat	Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	8 umol/min	0.0399 umol/min

Secondary

Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat

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

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

Arm	Measure	Group	Value (MEAN)
Daprodustat	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat	3 ug/min	-0.2560 ug/min
Daprodustat	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat	10 ug/min	6.8103 ug/min

Secondary

Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa

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

Population: PDPP Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Daprodustat	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	3 ug/min	0.3844 ug/min	Standard Deviation 0.52197
Daprodustat	Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa	10 ug/min	-0.2873 ug/min	Standard Deviation 1.11519

Secondary

Number of Participants Discontinuing the Randomized Study Treatment

Number of participants who discontinued the randomized study treatment were assessed.

Time frame: Up to Day 42

Population: Safety Population

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Participants Discontinuing the Randomized Study Treatment	0 Participants
Darbepoetin Alfa	Number of Participants Discontinuing the Randomized Study Treatment	0 Participants

Secondary

Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

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

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

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	Any AEs	0 Participants
Daprodustat	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	Any SAEs	0 Participants
Darbepoetin Alfa	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	Any AEs	1 Participants
Darbepoetin Alfa	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	Any SAEs	0 Participants

Secondary

Number of Participants With Any AE of Special Interest (AESI)

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

Population: Safety Population

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Participants With Any AE of Special Interest (AESI)	0 Participants
Darbepoetin Alfa	Number of Participants With Any AE of Special Interest (AESI)	0 Participants

Other Pre-specified

Absolute Values of Clinical Chemistry Parameters of Alanine Transaminase (ALT), Alkaline Phosphatase (ALP) and Aspartate Transaminase (AST)

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