Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Open-Label, Randomized, Active-Controlled Study of the Efficacy and Safety of Roxadustat (FG-4592) in the Maintenance Treatment of Anemia in Subjects With End Stage Renal Disease (ESRD) on Stable Dialysis
Brief Summary: The primary objective of this study is to evaluate the efficacy and safety of roxadustat compared with active control (epoetin alfa) for the maintenance treatment of anemia in participants with ESRD on dialysis.


Options:
A: Inclusion Criteria:

* Age (at the time of informed consent): \>=20 years of age
* Screening verification only: Stage of chronic kidney disease (CKD) (ND subjects only): CKD stages 3, 4, and 5 defined by estimated glomerular filtration rate (eGFR) using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) formula
* Dialysis:

  * Not on dialysis for at least 12 weeks prior to screening (ND subjects)
  * On peritoneal dialysis (PD subjects)
* Use of ESA:

  * ESA non-users: Have not used ESAs for 8 weeks prior to screening
  * ESA users: Have used the same ESA for 8 weeks prior to screening. However, in the ND subjects, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered once every 4 weeks and up to one-step dose change during 8 weeks prior to screening).
* Hgb: Determined at the site using an Hgb analyzer

  * ESA non-users: \>=8.0 g/dL and \<11.0 g/dL
  * ESA users: \>=9.0 g/dL and \<=13.0 g/dL
* Iron parameters: Ferritin \>100 nanograms per milliliters (ng/mL) or transferrin saturation (TSAT) \>20% (screening verification only)
* Gender (screening verification only): Female or male. Females: Not pregnant \[demonstrated to be negative for human chorionic gonadotropin (hCG) in urine or serum\], not breast-feeding, and meet at least one of the following:

  1. Females of non-childbearing potential are defined as follows:

     * Pre-menopausal with at least one of the following and no plans to utilize assisted reproductive techniques (e.g., in vitro fertilization or donor embryo transfer):
     * History of bilateral tubal ligation or salpingectomy
     * History of hysteroscopic tubal occlusion and postoperatively documented bilateral tubal obstruction
     * History of hysterectomy
     * History of bilateral oophorectomy
     * Postmenopausal defined as: females 60 years of age or older or ; In females \<60 years of age, 12 months of spontaneous amenorrhea (in questionable cases a blood sample with postmenopausal follicle stimulating hormone \[FSH\] and estradiol concentrations is confirmatory \[specified reference ranges\]). Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the most effective 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.
  2. Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in "GSK Listing of Most Effective Contraceptive Methods for Females of Childbearing Potential" from 28 days prior to the first dose of study medication until the completion of the follow-up visit (for subjects randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for subjects randomized to the Epoetin beta pegol group).
* Informed consent: Written informed consent, including adherence to the requirements and conditions specified in the consent form and the protocol, must be obtained from each subject as specified in Protocol.

Exclusion Criteria:

Chronic kidney disease (CKD)-related criteria

* Dialysis

  * Cohort 1 and Cohort 3: Start or plan to initiate dialysis during the study
  * Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
* Kidney transplant: Planned living-related kidney transplant during the study Anemia-related criteria
* Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
* Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic syndromes
* Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within 8 weeks prior to screening or during a period from screening to Day 1.

Cardiovascular disease-related criteria

* Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed within 8 weeks prior to screening or during a period from screening to Day 1.
* Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system
* QT interval corrected for heart rate (QTc) (screening verification only): QTc \>500 milliseconds (msec) or QTc \>530 msec in subjects with bundle branch block Note: QT interval corrected using the Bazett's formula (QTcB) will be used, and Electrocardiogram (ECG) can be mechanically or manually read.

Other disease-related criteria

* Liver disease (if any of the following occurs):

  * (Screening verification only) Alanine transaminase (ALT) \>2 times upper limit of normal (ULN)
  * (Screening verification only) Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%)
  * Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis) Note: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or Gilbert's syndrome) is acceptable if the subject otherwise meets entry criteria..
* Malignancy: History of malignancy within 2 years prior to screening, or currently receiving treatment for cancer, (PD subjects only) complex renal cystic \>3 centimeters (cm) (II F, III or IV based on the Bosniak classification) Note (ND subjects and PD subjects): The only exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=8 weeks before screening.
* In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically risky.

Concomitant medication and other study treatment-related criteria

* Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 to Week 4 Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. However, they must be continued throughout the screening phase from Day 1 to Week 4.
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product or epoetin beta pegol
* Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited during the study period (prohibited medications: strong inducers and inhibitor of Cytochrome P450 2C8 \[CYP2C8\])
* Prior investigational product exposure: Use of an investigational agent within 30 days or five half lives of the investigational agent (whichever is longer)
* Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment duration of \>30 days

General health-related criteria

* Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator (or subinvestigator) considers would put the subject 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:

* Women without childbearing potential
* Male or female subjects ≥ 18 years of age with anemia of chronic kidney disease (CKD) at screening
* Estimated glomerular filtration rate of \< 60 mL/min/1.73 m2 (Modification of Diet in Renal Disease \[MDRD\] or the formula according to Matsuo, et al)
* Not on dialysis and not expected to begin dialysis during the treatment period of the study (at least 16 weeks from randomization)
* Not treated with any erythropoiesis-stimulating agent (ESA) within 8 weeks before randomization
* Mean screening Hb concentration \</= 10.5 g/dL
* Body weight of 45 kg to 125 kg, inclusive, at screening

Exclusion Criteria:

* Subjects with significant acute or chronic bleeding, such as overt gastrointestinal bleeding
* Chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
* Previous or concurrent cancer except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated \> 3 years prior to randomization
* Subjects treated with any ESA within the 8 weeks before randomization
* Red blood cell (RBC) containing transfusion within the 8 weeks before randomization
* History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within the last 6 months from initial screening visit
* Severe rhythm or conduction disorders (e.g., HR \< 50 or \> 110 bpm, atrial flutter, prolonged QT \> 500 msec, third degree atrioventricular \[AV\] block)
* New York Heart Association Class III or IV congestive heart failure
* Severe hepatic insufficiency (defined as alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 3 x the upper limit of normal \[ULN\], total bilirubin \> 2 mg/dL, or Child-Pugh B and C) or active hepatitis, in the investigator's opinion
C: Inclusion Criteria:

* Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on 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 subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
* Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.
* Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening.
* Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
* Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 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.
* Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
* Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration.

Exclusion Criteria:

* Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization.
* Subject has received any dose of IV iron within 6 weeks prior to randomization.
* Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
* Subject has a known history of myelodysplastic syndrome or multiple myeloma.
* Subject 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 Chronic Kidney Disease (CKD).
* Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
* Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
* Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization.
* Subject has active or chronic gastrointestinal bleeding.
* Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
* Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
* Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
* Subject has known New York Heart Association Class III or IV congestive heart failure.
* Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
* Subject has one or more contraindications for treatment with darbepoetin alfa:

  * Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization).
  * Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients.
* Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
* Subject has a history of malignancy, except for 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.
* Subject 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).
* Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) \> Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
* Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
* Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study.
* Subject will be excluded from participation if any of the following apply:

  * subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or
  * any condition which makes the subject unsuitable for study participation.
* Subject 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.
* Subject has a history of alcohol or drug abuse within 2 years prior to randomization
D: Inclusion Criteria:

* Receiving dialysis for ESRD for ≥3 months. Incident dialysis participants (under Amendment 1 and 2) receiving dialysis for ESRD for ≥ 2 weeks but ≤ 4 months at the time of randomization
* Participants must be on ESA for ≥ 8 weeks prior to screening; incident dialysis participants must be on ESA for ≥ 4 weeks prior to screening.
* Mean of the 3 most recent central lab Hb values during the Screening Period must be ≥ 9.0 g/dL and ≤ 12.0 g/dL (for incident dialysis participants, mean of the 2 most recent Hb values must be ≥ 8.5 g/dL and ≤ 12.0 g/dL); with an absolute difference of ≤ 1.3 g/dL between the highest and the lowest value. Samples are obtained at least 4 days apart (2 days under Amendment 2) and the last Hb value must be within 10 days prior to the randomization visit
* Participants with ferritin level ≥ 100 nanograms (ng)/milliliter (mL) (\<100 ng/mL under Amendment 2) or transferrin saturation (TSAT) ≥ 20% (\<20% under Amendment 2) at screening may qualify upon receiving iron supplement (per local standard of care)
* Participants with a serum folate and Vitamin B12 ≥ lower limit of normal (LLN) (\< LLN under Amendment 2) at screening may qualify upon receiving supplement (per local standard of care)
* Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3x the upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5x ULN at screening
* Participant's body weight is 45 kilograms (kg) to 160 kg.

Exclusion Criteria:

* Participant has received an red blood cell (RBC) transfusion within 8 weeks (4 weeks under Amendment 2) prior to randomization
* Participant has known history of myelodysplastic syndrome or multiple myeloma
* Participant has known inherited disease such as thalassemia or sickle cell anemia or other known causes for anemia other than chronic kidney disease.
* Participant has known hemosiderosis, hemochromatosis, coagulation disorder,or hypercoagulable condition
* Participant has known chronic inflammatory disease that could cause anemia
* Participant has anticipated surgery that is expected to cause blood loss
* Participant has known gastrointestinal bleeding
* Participant has history of chronic liver disease (for example, chronic infectious hepatitis,chronic auto-immune liver disease,cirrhosis, or fibrosis of the liver)
* Participant with New York Heart Association (NYHA) Class III or IV congestive heart failure
* Participant has had a heart attack, stroke, seizure, or a thrombotic/thromboembolic event (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to participating in the study
* Participant has uncontrolled high blood pressure within 2 weeks prior to participating in the study
* Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥2 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.)
* Participant is positive for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or anti-hepatitis C virus antibody
* Participant with prior organ transplant who experience rejection within 6 months or on high doses of immunosuppressive therapy
* Participant has any of the following known untreated conditions; proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.

Answer: D