Anemia Studies in CKD: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat- Iron (ASCEND: Fe)

Daprodustat administration has the potential, by virtue of increasing hypoxia-inducible factor (HIF) levels, to increase oral iron absorption and incorporation into hemoglobin (Hgb). Therefore, the purpose of this study is to compare the effect of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on non-heme oral iron absorption using stable isotopic iron (57Fe and 58Fe) by measuring incorporation of iron in erythrocytes. This study will be a randomized, repeat dose, open label, two period cross-over study in adult, male and female participants with anemia associated with chronic kidney disease who are not on dialysis currently treated with stable doses less than or equal to (\<=) 50 percent (%) change in 4-weekly dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., epoetin alfa or darbepoetin alfa). Sufficient participants will be enrolled such that at least 12 participants comprise the Evaluable Population. The study will compare the fractional iron absorption between treatment arms (daprodustat and rhEPO \[i.e., epoetin alfa or darbepoetin alfa\]) and will evaluate the difference is equal/not equal to zero.


Eligibility Criteria:
Inclusion Criteria:

* Participants 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 Chronic kidney disease (CKD) (confirmed at Week-4 only) defined by estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Participants who are currently treated with stable doses (\<=50% change in 4-weekly dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., epoetin alfa or darbepoetin alfa).
* Participants with Hgb levels between 9.0 and 11.5 g/dL, inclusive, who meet the Hgb stability criteria.
* Participants may be on stable maintenance oral iron supplementation (less than \[\<\] 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 8 weeks prior to the Day 1 visit.
* Male or Female participants may participate. 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 agrees to follow the contraceptive guidance during the treatment period to the follow-up visit.
* Capable of giving signed informed consent.

Exclusion Criteria:

* On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (i.e., Day 1).
* Planned kidney transplant within 3 months after study start.
* A positive test for Human Immunodeficiency Virus (HIV) antibody.
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational products
* Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until the end of Treatment Period 2.
* Planned or current administration of methoxy polyethylene glycol (PEG)-epoetin beta.
* The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or 5 half lives, whichever is longer, from screening 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 outside the range between 100 and 500 nanogram per milliliter (ng/mL), inclusive, at screening.
* Transferrin saturation (TSAT) outside the range between 15% and 40%, inclusive, at Screening.
* Folate \< 2.0 ng/mL (4.5 nanomoles per liter \[nmol/L\]; may rescreen in a minimum of 8 weeks) at screening.
* High sensitivity C-reactive protein (hsCRP) \>=20 microgram per milliliter (μg/mL) at screening.
* Myocardial infarction or acute coronary syndrome: \<=8 weeks prior to screening through Day 1.
* Hospitalization for greater than 24 hours: \<=8 weeks prior to screening through Day 1
* Stroke or transient ischemic attack \<=8 weeks prior to screening through Day 1.
* Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
* Current uncontrolled hypertension as determined by the investigator.
* QT interval corrected for heart rate using Bazett's formula (QTcB): QTcB \>500 milliseconds (msec), or QTcB \> 530 msec in participants with Bundle Branch Block. There is no corrected QT interval (QTc) exclusion for participants with a predominantly paced rhythm.
* Active chronic inflammatory disease that could impact erythropoiesis.
* History of bone marrow aplasia or pure red cell aplasia.
* Conditions, other than anemia associated with chronic kidney disease, which can affect erythropoiesis.
* Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant gastrointestinal (GI) bleeding from \<=4 weeks prior to screening through Day 1.
* Liver disease (any of the following): Alanine transaminase (ALT) \>2 times upper limit of normal (ULN; screening only); Bilirubin \>1.5 times ULN (screening only). 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 (excluding vascular access surgery) within the 8 weeks prior to screening through Day 1, or planned during the study.
* Blood transfusion within 8 weeks prior to screening 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 4 weeks prior to screening through Day 1.
* History of malignancy within the two years prior to screening 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.
* 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.