Please select the eligibility criteria that correspond to the clinical trial below.
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
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.


Options:
A: Inclusion Criteria:

* Age: 18 to 99 years of age (inclusive)
* CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization.
* For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.
* \>=80% and \<=120% compliance with placebo during run-in period.
* Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions.

Exclusion Criteria:

* Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
* Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
* Ferritin: \<=100 nanograms (ng)/milliliter (mL) (\<=100 micrograms/liter \[L\]) at screening.
* Transferrin saturation (TSAT) (screening only): \<=20%.
* Aplasias: History of bone marrow aplasia or pure red cell aplasia.
* Other causes of anemia: untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
* Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant GI bleeding \<=4 weeks prior to screening through to randomization (Day 1).
* MI or acute coronary syndrome: \<=4 weeks prior to screening through to randomization (Day 1).
* Stroke or transient ischemic attack: \<=4 weeks prior to screening through to randomization (Day 1).
* Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
* Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator.
* Bazett's corrected QT interval (QTcB) (Day 1): QTcB \>500 millisecond (msec), or QTcB \>530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.
* Alanine transaminase (ALT): \>2x upper limit of normal (ULN) at screening.
* Bilirubin: \>1.5xULN at screening.
* Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
* Malignancy: History of malignancy within the 2 years prior to screening through to randomization (Day 1) or currently receiving treatment for cancer, or complex kidney cyst (example \[e.g.\] Bosniak Category II F, III or IV) \> 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=4 weeks prior to screening.
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or darbepoetin alfa.
* Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
* Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
* Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of \>30 days.
* Females only: Subject is pregnant \[as confirmed by a positive urine human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only\], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options.
* Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance (e.g., intolerance to darbepoetin alfa) or prevent understanding of the aims or investigational procedures or possible consequences of the study.
B: 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.
C: Inclusion Criteria:

* Subject with end-stage kidney disease (ESKD) on dialysis (including, hemodiafiltration, hemodialysis, and other modalities except for peritoneal dialysis) weekly or more than weekly
* Body weight \> 40 and ≤ 160 kg at screening
* Male or female subject ≥ 20 years of age at screening
* At least one kidney
* Not treated with ESAs and/or HIF-PH inhibitors within 8 weeks prior to randomization. However, in case of the patient washed out from ESAs, when the mean Hb (at least 2 central laboratory measurements must be taken ≥ 2 days apart before dialysis) has decrease to ≥ 0.5 dL from the Hb level (central laboratory measurement, before dialysis) after the last ESA administration, AND the interval from the last ESA administration to the study drug assignment was over 1 week for epoetin-alpha, 2 weeks for darbepoetin alpha or 4 weeks for epoetin beta pegol
* Mean of the last 2 Hb level (central laboratory measurement, before dialysis) during the screening period must be ≥ 8.0 and \< 10.0 g/dL (2 measurements must be taken ≥ 2 days apart and the difference between the 2 measurements must be \< 1.2 g/dL) with the last screening Hb measurement within 14 days prior to study drug assignment
* Ferritin ≥ 50 ng/mL at screening

Exclusion Criteria:

* New York Heart Association (NYHA) Class III or IV congestive heart failure
* History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, pulmonary thromboembolism, and acute limb ischemia) within 6 months prior to randomization
* Sustained and poorly controlled arterial hypertension (defined as systolic BP≥ 180mmHg or diastolic BP ≥ 110mmHg) or hypotension (defined as systolic BP \< 90mmHg) at randomization
* Proliferative choroidal or retinal disease, such as neovascular age-related macular degeneration or proliferative diabetic retinopathy requiring invasive treatment (e.g., intraocular injections or laser photocoagulation)
D: Inclusion Criteria:

* - Subjects are eligible if they meet all of the inclusion criteria below:
* General criteria
* Age: \>=18 years of age. (Week -4 verification only)
* Gender: Female and male subjects. (Week -4 verification only) Females: If of childbearing potential, must agree to use one of the approved contraception methods, from Screening until completion of the Follow-up Visit OR of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, or oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 International units per liter (IU/L) and estradiol \<=10 picomole per liter (pmol/L) is confirmatory\]. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the approved contraception methods if they wish to continue their HRT during the study. Otherwise they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2 weeks must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method;
* Q-T Interval Corrected for Heart Rate (QTc): Bazett's Correction of QT Interval (QTcB) \<470 millisecond (msec) or QTcB \<480 msec in subjects with bundle branch block. There is no QTc inclusion criterion for a subject with a predominantly paced rhythm.
* CKD-related criteria
* Dialysis frequency: On hemodialysis (HD) three to five times weekly for at least 4 weeks prior to Week -4 Screening through Week 4. NOTE: Combination methods including hemofiltration (HF) or ultrafiltration (UF) with HD are allowed. However, the type of dialysis (HD, hemodiafiltration (HDF) or UF) should not change during the study.
* Dialysis adequacy: A single-pool dialyzer clearance multiplied by dialyzer time divided by volume of distribution of urea (Kt/Vurea) of \>=1.2 based on a historical value obtained within the prior month in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio (URR) of at least 65%. NOTE: Only needs confirming at Week -4.
* Hemoglobin: Baseline Hgb of 9.0-11.5 g/dL (may rescreen in a minimum of 2 weeks).
* Stable rhEPO dose: Using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses varying by no more than 50% during the 4 weeks prior to Week -4. At Day 1 (randomization), confirm that total weekly doses varied by no more than 50% during the screening period.
* Iron replacement therapy: Subjects may be on stable maintenance oral or IV (\<=100 mg/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization.

Exclusion Criteria:

* Subjects are not eligible if they meet any of the exclusion criteria below:
* CKD-related criteria
* Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period.
* Renal transplant: Pre-emptive or scheduled renal transplant.
* High rhEPO dose: An epoetin dose of \>=360 IU/Kg/Week IV or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram (µg)/Kg/Week IV or SC within the prior 8 weeks through Day 1 (randomization).
* Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Day 1 (randomization).
* Laboratory test-based criteria (Week -4 verification only)
* Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
* Folate: \<2.0 nanogram (ng)/mL (\<4.5 nanomole (nmol)/L) (may rescreen in a minimum of 4 weeks).
* Ferritin: \<100 ng/mL (\<100 Micrograms per liter).
* Transferrin saturation (TSAT): Outside of the reference range.
* Cardiovascular disease-related criteria
* Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization).
* Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Week -4 Screening through Day 1 (randomization); Symptomatic right heart failure diagnosed prior to Week -4 Screening through Day 1 (randomization).
* Hypertension: Defined using pre-dialysis vitals (Week -4, Day 1) of diastolic blood pressure (DBP) \>100 millimeters of mercury (mmHg) or systolic blood pressure (SBP) \>170 mmHg.
* Thrombotic disease: History of thrombotic disease (e.g., venous thrombosis such as deep vein thrombosis or pulmonary embolism, or arterial thrombosis such as new onset or worsening limb ischemia requiring intervention), except vascular access thrombosis, within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* Other disease-related criteria
* Ophthalmology disease: Meeting any ophthalmologic-related exclusion criteria determined at the Screening ophthalmology exam.
* Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Week -4 Screening through Day 1 (randomization).
* Hematological disease: Any hematological disease including those affecting platelets, white or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia and thalassemia), coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or any other cause of anemia other than renal disease diagnosed prior to Week -4 Screening through Day 1 (randomization).
* Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence at Screening of abnormal liver function tests \[alanine transaminase (ALT) or aspartate transaminase (AST) \> 2.0 x upper limit of normal (ULN) or total bilirubin \> 1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study. NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions are not met.
* Major surgery: Major surgery (excluding vascular access surgery) within the prior 8 weeks, during the Week -4 Screening phase or planned during the study.
* Transfusion: Blood transfusion within the prior 8 weeks, during the Week -4 Screening phase or an anticipated need for blood transfusion during the study.
* GI Bleeding: Evidence of actively bleeding peptic, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* Acute infection: Clinical evidence of acute infection or history of infection requiring intravenous (IV) antibiotic therapy within the 8 weeks prior to Week -4 Screening through Day 1 (randomization). NOTE: IV antibiotics as prophylaxis are allowed.
* Malignancy: Subjects with a history of malignancy within the prior 5 years, who receiving treatment for cancer, or who have a strong family history of cancer (e.g., familial cancer disorders); with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to Week -4 Screening through Day 1 (randomization).
* Concomitant medication and other Investigational Product-related criteria
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
* Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Week -4 Screening until the Follow-up Visit.
* Prior investigational product exposure: The Subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days from Week -4 Screening through Day 1 (randomization).
* General health-related criteria
* Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk.
* Pregnancy or Lactation: Pregnant females as determined by positive serum human chorionic gonadotropin (hCG) test OR women who are lactating at Week -4 Screening or during the trial.
* Other Eligibility Criteria Considerations
* Laboratory eligibility criteria will be assessed according to the central laboratory results for the screening samples.
* Subjects who fail screening may be rescreened as soon as the investigator feels they may have become eligible. However, an individual subject may not rescreen more than twice. There is no predetermined amount of time that the investigator needs to wait to rescreen a previously ineligible subject, except those excluded for Hgb or folate who may only rescreen in 2 and 4 weeks, respectively, and those excluded for Vitamin B12 who may rescreen in 8 weeks

Answer: B