Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Non-dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Darbepoetin Alfa
Brief Summary: The purpose of this multi-center event-driven study in non-dialysis (ND) participants with anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa.


Options:
A: 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.
B: Inclusion Criteria:

* Subjects who were diagnosed with non-dialysis Chronic Kidney Disease and who are considered not to require renal replacement therapy during the study period
* Subjects with renal anemia who have been receiving erythropoiesis stimulating agent (ESA) by subcutaneous injection and whose Hb values are considered stable.
* Mean of the subject's two most recent Hb values before randomization during the Screening Period must be ≥10.0 g/dL and ≤12.0 g/dL
* Either transferrin saturation ≥ 20% or serum ferritin ≥ 100 ng/mL
* Female subject must either:

Be of non-childbearing potential:

* post-menopausal, or
* documented surgically sterile Or, if of childbearing potential,
* Agree not to try to become pregnant during the study and for 28 days after the final study drug administration
* And have a negative urine pregnancy test at pre-screening
* And, if heterosexually active, agree to consistently use two forms of highly effective birth control\* (at least one of which must be a barrier method) starting at pre-screening and throughout the study period and continued for 28 days after the final study drug administration.

  * Female subject must agree not to breastfeed starting at pre-screening and throughout the study period, and continued for 28 days after the final study drug administration.
  * Female subject must not donate ova starting at pre-screening and throughout the study period, and continued for 28 days after the final study drug administration.
  * Male subject and their female spouse/partners who are of childbearing potential must be using two forms of highly effective birth control (at least one of which must be a barrier method) starting at pre-screening and continue throughout the study period, and for 12 weeks after the final study drug administration
  * Male subject must not donate sperm starting at pre-screening and throughout the study period and, for 12 weeks after the final study drug administration

Exclusion Criteria:

* Concurrent retinal neovascular lesion untreated or macular edema untreated, and patients with any condition that significantly compromises the ability to visualize the retina
* Concurrent autoimmune disease with inflammation that could impact erythropoiesis
* History of gastric/intestinal resection considered influential on the absorption of drugs in the gastrointestinal tract (excluding resection of gastric or colon polyps) or concurrent gastro-paresis
* Uncontrolled hypertension
* Concurrent congestive heart failure (NYHA Class III or higher)
* History of hospitalization for treatment of stroke, myocardial infarction, or pulmonary embolism within 12 weeks before the pre-screening assessment
* Positive for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibody at the pre-screening assessment, or positive for human immunodeficiency virus (HIV) in a past test
* Concurrent other form of anemia than renal anemia
* History of pure red cell aplasia
* Having received treatment with protein anabolic hormone, testosterone enanthate, or mepitiostane within 6 weeks before the pre-screening assessment
* Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), or total bilirubin that is greater than the criteria, or previous or concurrent another serious liver disease at pre-screening assessment
* Previous or current malignant tumor (no recurrence for at least 5 years is eligible.)
* Having undergone red blood transfusion and/or a surgical procedure consider to promote anemia and/or ophthalmological surgery within 4 weeks before the pre-screening assessment
* Having undergone a kidney transplantation
* History of serious drug allergy including anaphylactic shock
* Having a previous history of treatment with ASP1517 or participation in this study
* Participation in another clinical study or post-marketing clinical study (including that of a medical device) within 12 weeks before informed consent acquisition
C: Inclusion Criteria:

1. Subject has voluntarily signed and dated an informed consent form
2. Age 18 to 75 years
3. End-stage renal disease (ESRD) and receiving maintenance hemodialysis TIW for ≥4 months prior to Day 1
4. Hemoglobin (Hb) values in 4 screening visits and the mean Hb must be between 9.0 and 12.0 g/dL (inclusive), and the difference between them must be ≤1.5 g/dL.
5. Stable doses of IV or Subcutaneous injection of epoetin alfa, defined as follows:

   * Epoetin alfa dose range for 6 weeks prior to Day -7:

     3000 to 20,000 IU/week
   * Stable doses of epoetin alfa (i.e., the maximum epoetin alfa dose does not exceed 130% of the lowest dose of epoetin alfa taken in this period)
6. Complete Blood Count (CBC), Hematology, liver function blood tests within acceptable limits
7. Serum folate and vitamin B12 levels above the lower limit of normal (LLN)
8. Body weight: 40 to 100 kg (dry weight) inclusive
9. Body mass index (BMI): 16 to 38 kg/m2 inclusive
10. HD subjects: dialysis vascular access via native arteriovenous fistula or synthetic graft (not via catheter)

Exclusion Criteria:

1. Anticipated change in hemodialysis prescription or access during the screening or dosing period of the study
2. Any clinically significant infection or evidence of an underlying infection such as a white blood cell count (WBC) \> ULN during screening on two separate occasions,
3. Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); anti-hepatitis C virus antibody (anti-HCV Ab)
4. History of chronic liver disease
5. New York Heart Association Class III or IV congestive heart failure
6. Chronic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
7. Active or chronic gastrointestinal bleeding, or a known coagulation disorder
8. Hemoglobinopathy (e.g., homozygous sickle-cell disease, thalassemia of all types, etc.)
9. Hematological disorders, including myelodysplastic syndrome, multiple myeloma, or pure red cell aplasia
10. History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
11. Active hemolysis or diagnosis of hemolytic syndrome
12. Known bone marrow fibrosis
13. Uncontrolled or symptomatic secondary hyperparathyroidism (PTH\>600ng/L)
14. Any prior organ transplantation
15. Drug-treated gastroparesis, short-bowel syndrome, or any other gastrointestinal condition that may lead to reduced absorption of study drug
16. History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the subject
17. Prior treatment with FG-4592
18. Use of traditional Chinese medicines (TCM) during the screening visit to Day 1 or plans to use TCM during the study unless approved in advance by the Medical Monitor
D: 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.

Answer: D