Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Single-blind, Placebo-controlled, 4-Week Treatment Study of the Safety and Biologic Activity of Escalating Multiple Oral Doses of FG-4592 in Subjects With Chronic Kidney Disease Not Requiring Dialysis
Brief Summary: The primary objective of the study is to evaluate the safety, tolerability, and pharmacodynamic effects of different oral doses of roxadustat administered 2 times a week (BIW) or 3 times a week (TIW) for up to 4 weeks to participants with chronic kidney disease (CKD) not requiring dialysis.


Options:
A: Key Inclusion Criteria:

* ESRD and receiving maintenance HD TIW for ≥4 months prior to Day 1
* Two most recent Hb values obtained during screening period must be within the ranges set below:

  i) Group A. Normoresponder Criteria: Hb range in the 8 weeks prior to randomization within 9.0 to 13.5 g/dL ii) Group B. Hyporesponder Criteria: Hb range in the 8 weeks prior to randomization within 8.5 to 13.5 g/dL
* Epoetin alfa, dose requirements:

  i) Group A. Normoresponder Criteria - Cohorts A-1 to A-12: Stable IV epoetin alfa dose at baseline (that is, no more than a 30% fluctuation in the weekly dose) during the 4 weeks prior to study Day -3
  1. Cohorts A-1 to A-4: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 85 IU/kg/dose, TIW; weekly dose between 75 and 255 IU/kg/week
  2. Cohort A-5: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 115 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week
  3. Cohort A-9: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 150 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week
  4. Cohorts A-6 to A-8: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 115 IU/kg/dose, TIW, and two times a week (BIW); total weekly dose between 75 and 345 IU/kg/week
  5. Cohorts A-10 to A-12: Optional cohorts to be decided (TBD), dosing frequency and dose range to be determined by sponsor ii) Group B. Hyporesponder Criteria:

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  1. Cohort B-1 (completed): Current and previous (past 4 weeks) epoetin alfa dose range 125 to 400 IU/kg/dose, TIW; weekly dose between 375 and 1200 IU/kg/week
  2. Cohort B-2 to B-4: Current and previous (past 4 weeks) epoetin alfa dose range \>115 IU/kg/dose, TIW; total weekly dose \>345 IU/kg/week no requirement for stability of epoetin alfa doses
* Complete Blood Count (CBC), Hematology, liver function blood tests, serum folate and vitamin B12 within acceptable limits
* Absence of active or chronic gastrointestinal bleeding
* High sensitivity C-reactive protein (hsCRP) \<60 mg/liter for normoresponders Cohorts A-8 through A-12 enrolled under Amendment 3; no hsCRP criteria for hyporesponders
* Body weight: 40 to 140 kg (dry weight)
* Body mass index (BMI): 18 to 45 kg/meter square (m\^2)
* Dialysis vascular access via native arteriovenous fistula or synthetic graft, or permanent (tunneled) catheter (not via temporary catheter); permanent and temporary catheters, however, are still prohibited in Cohort A-5

Key Exclusion Criteria:

* Anticipated change in HD prescription
* Any clinically significant infection or evidence of an underlying infection
* Positive for any of the following: Human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab)
* History of chronic liver disease
* New York Heart Association Class III or IV congestive heart failure
* Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
* History of myelodysplastic syndrome
* History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
* Active hemolysis or diagnosis of hemolytic syndrome
* Known bone marrow fibrosis
* Uncontrolled or symptomatic secondary hyperparathyroidism
* Any prior organ transplantation
* Drug-treated gastroparesis or short-bowel syndrome
* History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the participant
* Prior treatment with roxadustat
* Diagnosis or suspicion of renal cell carcinoma
* Red blood cell (RBC) transfusion within 12 weeks prior to Day 1, or anticipated need for RBC transfusion during the dosing period
* IV iron supplement within 2 weeks prior to Day 1 and/or unwilling to withhold IV iron during the dosing/treatment period
B: Inclusion criteria:

* Participant has a diagnosis of chronic kidney disease, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not receiving dialysis; with an Estimated Glomerular Filtration Rate (eGFR) \<60 mL/min/1.73 m\^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
* The mean of the Participant's three most recent Hb values during the Screening period, obtained at least 4 days apart, must be less than or equal to 10.0 g/dL, with a difference of less than or equal to 1.0 g/dL between the highest and the lowest values. The last Hb value must be within 10 days prior to randomization.
* Participant has a ferritin level greater than or equal to 30 ng/mL (greater than or equal to 67.4 pmol/L) at screening.
* Participant has a transferrin saturation (TSAT) level greater than or equal to 5% at screening.
* Participant has a serum folate level greater than or equal to lower limit of normal at screening.
* Participant has a serum vitamin B12 level greater than or equal to lower limit of normal at screening.
* Participant's alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN.
* Participant's body weight is 45.0 kg up to a maximum of 160.0 kg.

Exclusion criteria:

* Participant has received any ESA treatment within 12 weeks prior to randomization.
* Participant has had more than one dose of IV iron within 12 weeks prior to randomization.
* Participant has received a RBC transfusion within 8 weeks prior to randomization.
* Participant has a known history of myelodysplastic syndrome or multiple myeloma.
* Participant has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD.
* Participant has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
* Participant has chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
* Participant is anticipated to have elective surgery that is expected to lead to significant blood loss or anticipated elective coronary revascularization.
* Participant has active or chronic gastrointestinal bleeding.
* Participant has received any prior treatment with roxadustat or a hypoxia-inducible factor Prolyl Hydroxylase Inhibitor (HIF-PHI).
* Participant has been treated with iron-chelating agents within 4 weeks prior to randomization.
* Participant has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver)
* Participant has a known New York Heart Association Class III or Intravenous (IV) congestive heart failure.
* Participant has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., pulmonary embolism) within 12 weeks prior to randomization.
* Uncontrolled hypertension or two or more blood pressure (BP) values of systolic BP (SBP) greater than or equal to 160 mmHg or diastolic BP (DBP) greater than or equal to 95 mmHg confirmed by repeat measurement within 2 weeks prior to randomization.
* Participant has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma on renal ultrasound within 12 weeks prior to randomization.
* Participant has a history of malignancy, except the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
* Participant is positive for any of the following: Human Immunodeficiency Virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab).
* Participant has an active clinically significant infection manifested by White Blood Count (WBC) \> ULN, and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
* Participant has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration and retinal vein occlusion.
* Participant has had any prior organ transplant (that has not been explanted) or a scheduled organ transplantation.
* Participant has participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to the initiation of Screening.
* Participant has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen (paracetamol) \> 2.0 g/day during the treatment or follow-up period of the study.
* Participant has a history of alcohol or drug abuse within 2 years prior to randomization.
C: Inclusion Criteria:

* ≥18 years of age
* Diagnosis of chronic kidney disease (CKD) with an estimated glomerular filtration rate ≤60 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) at Screening and not expected to start dialysis within 6 months of Screening
* Mean Screening hemoglobin \<10.0 grams per deciliter (g/dL)
* Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening

Exclusion Criteria:

* Anemia due to a cause other than CKD or participants with active bleeding or recent blood loss
* Red blood cell transfusion within 8 weeks prior to randomization.
* Any erythropoietic stimulating agent within 8 weeks prior to randomization
* Uncontrolled hypertension
* Severe heart failure at Screening (New York Heart Association Class IV)
* Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for heart failure, or stroke within 12 weeks prior to or during Screening
* Hypersensitivity to Darbepoetin or Vadadustat or to any of their excipients
D: Inclusion Criteria:

1. 18 to 80 years of age. Participants aged over 75 years but otherwise meet all other participant selection criteria will be evaluated on a case-by-case basis and can be included in this study, per discretion of Sponsor's physician representative such as medical monitor or clinical leader.
2. Chronic Kidney Disease Stage 3 or 4 with hemoglobin \<11.0 grams (g)/deciliter (dL).
3. Normal iron studies.
4. Normal folate and vitamin B12 levels.
5. Liver function tests within normal limits at screening.
6. Absence of active or chronic rectal bleeding.
7. Absence of diagnosis of age-related macular degeneration (AMD), diabetic macular edema, or diabetic proliferative retinopathy that is likely to require treatment during the trial.
8. Female participants must not be pregnant nor breastfeeding and agree to use acceptable method of contraception.
9. Male participants with partners who can have children must agree to use a medically acceptable method of contraception.

Exclusion Criteria:

1. Seropositive for HIV.
2. History of chronic liver disease.
3. History of polycystic kidney disease (PKD).
4. Uncontrolled hypertension (diastolic BP \>110 millimeter of mercury (mmHg) or systolic BP \>170 mmHg at screening).
5. New York Heart Association Class III or IV congestive heart failure.
6. Recent myocardial infarction or acute coronary syndrome.
7. History of myelodysplastic syndrome.
8. Any history of malignancy or a known genetic predisposition for developing cancer (for example, with diagnostic markers suggesting a genetic predisposition of cancer) except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps.
9. Active inflammatory infection or chronic inflammatory disease.
10. Any clinically significant and uncontrolled medical condition considered a high risk for participation in an investigational study.
11. Blood clots within 4 weeks.
12. History of ongoing hemolysis or diagnosis of hemolytic syndrome.
13. Known history of bone marrow fibrosis.
14. History of hemosiderosis or hemochromatosis.
15. Androgen therapy within 12 weeks.
16. Red blood cell transfusion within 12 weeks.
17. Therapy with an erythropoiesis stimulating agent (ESA) such as human recombinant erythropoietin within the past 60 days.
18. Intravenous iron supplementation within the past 60 days.
19. Currently taking dapsone or acetaminophen \>2.6 g/day.
20. History of prior organ transplantation.
21. Alcohol consumption greater than 3 or more drinks per day within the past year.
22. Use of an investigational medication or participation in an investigational study within 4 weeks preceding Day 1.
23. Positive urine toxicology screen for a substance that has not been prescribed for the participant.

Answer: D