Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1b, Randomized, Open-Label Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Hemodialysis Subjects With Anemia Associated With Chronic Kidney Disease
Brief Summary: This study will be conducted to assess the pharmacokinetics of vadadustat 600, 750, and 900 milligrams daily, and intravenous erythropoiesis-stimulating agent (darbepoetin alfa or epoetin alfa), in hemodialysis participants with anemia associated with chronic kidney disease.


Options:
A: Inclusion 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. 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.
* Corrected QT interval (QTc): Bazett's Correction of QT Interval (QTcB) \<470 milliseconds (msec) or QTcB \<480 msec in subjects with bundle branch block. There is no QTc criterion for subjects with a predominantly paced rhythm.
* CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 defined by electronic estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Hgb: Group 1 (rhEPO naïve): Baseline Hgb of 8.0-11.0 g/dL (inclusive) (USA sites only: 8.0-10.0 g/dL, inclusive); Group 2 (rhEPO users): Baseline Hgb of 9.0-11.5 g/dL (inclusive) (USA sites only: 9.0-10.5, inclusive).
* Stable rhEPO dose for rhEPO users: Group 2 subjects must be using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses that varied 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.
* Oral iron therapy: If on oral iron, then doses must not be changed for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization.

Exclusion Criteria:

* Dialysis: On dialysis or planning to initiate dialysis during the study.
* Renal transplant: Pre-emptive or scheduled renal transplant.
* High rhEPO dose: An epoetin dose of \>=360 IU/kg/week intravenous (IV) or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram per kilogram per week (mcg/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).
* IV iron therapy: Use of IV iron for 4 weeks prior to Screening Week -4, during the screening phase, and through the first 4 weeks after Randomization
* Vitamin B12: Below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
* Folate: \<2.0 nanogram per millilitre (ng/mL) (\<4.5 nanomoles per liter \[nmol/L\]) (may rescreen in a minimum of 4 weeks).
* Ferritin: \<40 ng/mL (\<40 mcg/L).
* Transferrin saturation (TSAT): Below the lower limit of the reference range
* 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).
* Uncontrolled hypertension: Defined as diastolic blood pressure (DBP) \>100 mmHg or systolic blood pressure (SBP) \>170 mmHg at Week -4 and reconfirmed at Day 1.
* 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).
* 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.
* 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.
* Gastrointestinal (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 IV antibiotic therapy within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* 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).
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (see GSK1278863 IB for list of excipients and rhEPO (refer to local product labelling for details).
* 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).
* Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk.
* Patient participation: Unwillingness or inability of the subject to follow the procedures or lifestyle or dietary restrictions outlined in the protocol.
* Pregnancy or Lactation: Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test OR women who are lactating at Week -4 Screening or during the trial.
B: 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
* Currently maintained on erythropoiesis-stimulating agents therapy, with a dose received within 6 weeks prior to or during Screening
* Mean Screening hemoglobin between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the United States (US) and between 9.0 and 12.0 g/dL (inclusive) outside of the US
* 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 participant with active bleeding or recent blood loss
* Red blood cell transfusion 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
C: Inclusion Criteria:

* Patients who diagnosed as a end-stage kidney disease (ESKD) and are receiving stable chronic maintenance dialysis 3 times per week for ≥ 12 weeks
* Patients who are receiving ESA for at least 8 weeks and the dose of ESA is within the dose range of ESA label
* Hb value at screening test is ≥10.0 g/dL
* Receiving hemodialysis via arteriovenous fistula (AVF) or arteriovenous graft (AVG) or via permanent catheter
* Most recent two Hb values before dialysis during washout period must be both \<9.5 g/dL and one of two Hb values must be tested on first visit of the week

Exclusion Criteria:

* Proliferative retinopathy, age-related macular degeneration, retinal vein occlusion and/or macular edema that is considered to require treatment
* Immunological disease with severe inflammation as assessed by the Investigator; even if the inflammation is in remission, the subject is excluded (e.g. lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, celiac disease, etc)
* Having a history of gastric/intestinal resection considered influential on the absorption of the drug in the gastrointestinal tract or active gastroparesis
* Uncontrollable hypertension (SBP ≥160 mmHg and DBP ≥110 mmHg, before dialysis, at screening test)
* Congestive heart failure (NYHA classification III or higher)
* Having a history of hospitalization for stroke, myocardial infarction or lung infarction within 24 weeks before 1st registration
* Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab)
* Anemia other than anemia due to low/absent renal production of EPO (e.g., iron deficiency anemia, hemolytic anemia, pancytopenia, etc)
* Pure red cell aplasia
* Using anabolic androgenic steroid, testosterone enanthate or mepitiostane within 6 weeks before 1st registration
D: Inclusion Criteria:

* Male or female ≥18 years of age at the time of informed consent
* Receiving chronic, outpatient in-center hemodialysis three times a week for end-stage renal disease for at least 12 weeks prior to Screening
* Maintained on intravenous erythropoiesis-stimulating agent (ESA) therapy (mean dose of \<1.5 micrograms per kilogram per week for darbepoetin alfa, or mean dose of \<300 Units per kilogram per week for epoetin alfa) for 8 weeks prior to randomization
* Two hemoglobin values between 8.5 and 10.5 grams per deciliter, inclusive, measured at least 4 days apart within 28 days prior to randomization
* Investigator determines the participant is not likely to need rescue therapy (ESA administration or red blood cell transfusion) or require interruption or discontinuation of study drug within the next 30 days
* Serum ferritin ≥100 nanograms per milliliter and transferrin saturation ≥20% within the 28-day screening period prior to randomization
* Folate and vitamin B12 measurements ≥ lower limit of normal within the 28-day screening period prior to randomization
* Hemodialysis adequacy (Kt/Vurea) as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 12 weeks prior to randomization
* Female participants of childbearing potential who are non-lactating, not pregnant as confirmed by a negative serum pregnancy test at Screening within 9 days prior to dosing on Day 1, and using, and agree to continue using, an acceptable method of contraception for at least 4 weeks prior to first dose of study drug until 30 days after the last dose of study drug. Acceptable contraceptive use is outlined in the protocol.
* Female participants of non-childbearing potential who are either surgically sterile (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) or post-menopausal (\>12 months of spontaneous and continuous amenorrhea in a female \>55 years old, or \>12 months of spontaneous and continuous amenorrhea with a follicle stimulating hormone \[FSH\] level \>40 International Units per Liter in a female \<55 years old)
* Female participants of childbearing potential who agree not to donate ova during the study and for at least 30 days after the last dose of study drug
* Male participants who have not had a vasectomy must agree to use an acceptable method of contraception from time of first dose of study drug until 30 days after the last dose of the study drug, and to not donate sperm during the study and for at least 30 days after the last dose of study drug. Acceptable contraceptive use is outlined in the protocol.
* Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure

Exclusion Criteria:

* Treated with any HMG-CoA reductase inhibitor (statin) other than atorvastatin, pravastatin, simvastatin, or rosuvastatin within the 28-day screening period prior to randomization. Within the 28-day screening period prior to randomization, the maximum allowable dose of simvastatin is 20 milligrams (mg) daily, and the maximum allowable dose of rosuvastatin is 10 mg daily. These restrictions also apply to the dosing period.
* Treated with clinically relevant substrates of the breast cancer resistant protein (BCRP) transporter (e.g., sulfasalazine, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, topotecan, tenofovir, glecaprevir, pibrentasir, or sofosbuvir) within 30 days prior to randomization
* Anemia with a cause other than chronic kidney disease (e.g., sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia)
* Active bleeding or blood loss within 8 weeks prior to randomization
* Red blood cell transfusion within 8 weeks prior to randomization
* Anticipated to discontinue hemodialysis or change dialysis modality during the study
* History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver)
* Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin \>1.5× upper limit of normal (ULN) within the 28-day screening period prior to randomization. Participants with a history of Gilbert's syndrome may participate in the study if they are not jaundiced, have a total bilirubin \<3 × ULN and AST and ALT are not \>1.5× ULN.
* Current uncontrolled hypertension that would contraindicate the use of darbepoetin alfa or epoetin alfa as determined by the investigator
* 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 (HF) or New York Heart Association Class IV HF, or stroke within 12 weeks prior to randomization
* History of new or recurrent malignancy within 2 years prior to Screening or currently receiving treatment or suppressive therapy for cancer. Participants with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ may participate on the study.
* History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to randomization
* History of hemosiderosis or hemochromatosis
* History of bilateral native nephrectomy
* History of functioning organ transplantation other than corneal transplant
* Scheduled organ transplant from a living donor or on the kidney transplant wait list or expected to receive a transplant during the study
* History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)
* Known hypersensitivity to vadadustat excipients, or to darbepoetin alfa or epoetin alfa
* Use of an investigational drug within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization
* Prior administration of an hypoxia-inducible factor prolyl-hydroxylase, including vadadustat
* Any other reason, which in the opinion of the investigator, would make the participant not suitable for participation in the study
* Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration

Answer: D