Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment of Anemia in Hemodialysis Subjects Converting From Epoetin Alfa (FO2RWARD-2)
Brief Summary: This is a Phase 2 open-label efficacy, safety, and pharmacokinetic/pharmacodynamic (PK/PD) study to evaluate oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy.


Options:
A: Inclusion Criteria:

* ≥18 years of age, providing informed consent
* Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal disease for at least 12 weeks prior to Screening
* Maintained on intravenous Epoetin Alfa therapy for 8 weeks prior to and including Screening through Screening Visit 2 (SV2)
* Eligibility in the Main study and erythropoiesis-stimulating agent (ESA) hyporesponder parallel study is based on the following mean weekly Epoetin Alfa doses:

  1. Main study: Mean weekly Epoetin Alfa dose \<300 Units per kilogram per week (U/kg/week) for 8 weeks prior to SV2;
  2. ESA hyporesponder parallel study: Mean weekly Epoetin Alfa dose ≥300 U/kg/week for 8 weeks prior to SV2
* Two Hb values measured by the central laboratory at least 4 days apart between Screening Visit 1 (SV1) and SV2 as indicated:.

  1. Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive;
  2. ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 grams per deciliter (g/dL), inclusive
* Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening
* Folate and vitamin B12 measurements ≥ lower limit of normal during Screening
* Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 8 weeks prior to or during Screening
* Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure

Exclusion Criteria:

* Anemia due to 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 recent blood loss within 8 weeks prior to randomization
* Red blood cell (RBC) transfusion within 8 weeks prior to randomization
* Anticipated to discontinue hemodialysis during the study
* Judged by the Investigator that the participant is likely to need rescue therapy (ESA administration or RBC transfusion) immediately after enrollment in 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 x upper limit of normal (ULN) during Screening. Participants with a history of Gilbert's syndrome are not excluded.
* Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of Epoetin Alfa
* 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 or during Screening
* History of new or recurrent malignancy within 2 years prior to and during 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 are not excluded.
* History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening
* History of hemosiderosis or hemochromatosis
* History of prior organ transplantation (participants with a history of failed kidney transplant or corneal transplants are not excluded)
* Scheduled organ transplant from a living donor and participants on the kidney transplant wait-list who are expected to receive a transplant within 6 months
* History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)
* Known hypersensitivity to Vadadustat, Epoetin Alfa, or any of their excipients
* Any prior use of a hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitor or any use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to randomization
* For female participants of non-childbearing potential:

  1. inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) at least 1 month prior to Screening;
  2. not considered post-menopausal (no menses for \>1 year with follicle stimulating hormone \>40 U/Liter at Screening)
* For female participants of childbearing potential:

  1. lack of confirmation of the use of acceptable forms of contraception\* for a minimum of one complete menstrual cycle prior to Screening;
  2. positive serum pregnancy test at SV2;
  3. unwilling to use two acceptable forms of contraception\* (at least one of which must be a barrier method) starting Baseline/Day 1, throughout the Treatment Period and for 30 days after the final study drug administration
* Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the final study drug administration
* Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after the final study drug administration
* Male participants who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception\* during the study and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of Vadadustat
* Participants with bilateral native nephrectomy
* Any other reason, which in the opinion of the Investigator, would make the participant not suitable for participation in the study

  * Acceptable forms of contraception include:

    * Established use of oral, injected or implanted hormonal methods of contraception;
    * Placement of an intrauterine device or intrauterine system;
    * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
B: Inclusion Criteria:

* Mean of the subjects' two most recent Hb values during the Screening Period must be ≤10.0 g/dL with an absolute difference ≤1.0 g/dL between the two values
* Either transferrin saturation (TSAT) ≥ 5% or serum ferritin ≥ 30 ng/mL during the screening period
* Female subject must either:

Be of non-childbearing potential:

* post-menopausal (defined as at least 1 year without any menses) prior to Screening, 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 pregnancy test at Screening
* And, if heterosexually active, agree to consistently use two forms of highly effective form of birth control (at least one of which must be a barrier method) starting at 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 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 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 form of birth control (at least one of which must be a barrier method) starting at 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 Screening and throughout the study period and, for 12 weeks after the final study drug administration

Exclusion Criteria:

* Concurrent retinal neovascular lesion requiring treatment and macular edema requiring treatment
* 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 gastroparesis
* 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 screening assessment
* Positive for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibody at the screening assessment, or positive for human immunodeficiency virus (HIV) in a past test
* Concurrent other form of anemia than renal anemia
* Having received treatment with protein anabolic hormone, testosterone enanthate, or mepitiostane within 6 weeks before the 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 screening assessment
* Previous or current malignant tumor (no recurrence for at least 5 years is eligible.)
* Having undergone blood transfusion and/or a surgical procedure considered to promote anemia (excluding shunt reconstruction surgery for access to the blood) within 4 weeks before the screening assessment
* Having undergone a kidney transplantation
* Having a previous history of treatment with ASP1517.
* History of serious drug allergy including anaphylactic shock
* Participation in another clinical study or post-marketing clinical study (including that of a medical device) within 12 weeks before informed consent acquisition
C: Key Inclusion Criteria:

* 18 to 79 years of age, inclusive
* Chronic Kidney Disease (eGFR \<60 mL/min), not yet on dialysis
* Hemoglobin (Hgb) ≤ 10.5 g/dL
* Transferring saturation ≥ 20%
* Ferritin ≥ 50 ng/mL

Key Exclusion Criteria:

* Body mass index \>42
* Red blood cell transfusion within 12 weeks
* Androgen therapy within the previous 21 days prior to study dosing
* Therapy with any approved or experimental erythropoiesis stimulating agent (ESA) within the 11 weeks prior to the Screening visit
* Participants meeting the criteria of ESA resistance within the previous 4 months
* Individual doses of intravenous iron of greater than 250 mg within the past 21 days
* Aspartate aminotransferase or alanine aminotransferase \>1.8x upper limit of normal (ULN)
* Alkaline phosphatase \>2x ULN
* Total bilirubin \>1.5x ULN
* Uncontrolled hypertension
* New York Heart Association Class III or IV congestive heart failure
* Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to dosing
D: Inclusion Criteria:

* More than or equal to 18 years of age, at the time of signing the informed consent.
* Hemoglobin: Stable Hemoglobin 9.0 - 11.5 gram per deciliter (g/dL).
* Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three to five times weekly for at least 4 weeks prior to Day -28 Screening through Day 29.
* Dialysis adequacy: A single pool Kt/Vurea of \>=1.2 based on a historical value obtained within the prior three months in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio (URR) of at least 65 percent. NOTE: Only needs confirming at Day -28.
* Erythropoiesis-stimulating agent (ESA)dose: Treated with the same ESA (epoetins or their biosimilars, or darbepoetin or methoxy polyethylene glycol \[PEG\]-epoetin beta) with total weekly dose varying by no more than 50 percent during the 4 weeks prior to Day -28.
* Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous (IV) (\<=100 milligram (mg)/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Day -28, during the screening phase, and through the 29 days of treatment.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in study protocol.

Exclusion Criteria:

* Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period.
* Renal transplant: Planned for living-related kidney transplant.
* High ESA dose: An epoetin dose of \>=360 international unit (IU)/kilogram (kg)/week IV or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram (mcg)/kg/week IV or SC or methoxy PEG-epoetin beta dose of \>= 2.2 mcg/kg/week within the prior 8 weeks through Day 1 (randomization).
* Administration of methoxy PEG-epoetin beta within the prior 4 weeks through Day 1 (randomization).
* Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization).
* Stroke or transient ischemic attack: Within 8 weeks prior to Screening though Day 1 (randomization).
* Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Screening through Day 1 (randomization).
* Correction of Q-T Interval using Bazett's formula (QTcB): QTcB \>500 millisecond (msec) or QTcB \>530 msec in subjects with Bundle Branch Block. There is no correction of Q-T Interval (QTc) exclusion for subjects with a predominantly paced rhythm.
* Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to 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 of chronic disease other than renal disease diagnosed prior to Screening though 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 \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2x upper limit of normal (ULN) or total bilirubin \>1.5xULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participating in the study.

NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions are not met.

* Major surgery: Major surgery (excluding vascular access surgery) within the 8 weeks prior to Screening, during the Screening phase, or planned during the study.
* Transfusion: Blood transfusion within the 8 weeks prior to Screening, during the 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 Screening through Day 1 (randomization).
* Acute Infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 4 weeks prior to Screening through Day 1 (randomization). NOTE: IV antibiotics as prophylaxis are allowed.
* Malignancy: History of malignancy within the two years prior to randomization or currently receiving treatment for cancer, or has a known \>=4 centimeter complex kidney cyst (i.e. Bosniak Category II F, III of IV). NOTE: ONLY exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=8 weeks prior to Screening.
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product
* Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited (as per protocol) from 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 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, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
* Females ONLY: A female subject is not eligible to participate if she is pregnant \[as confirmed by a positive serum human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only\], breastfeeding, and if of reproductive potential does not agree to follow one of the options listed in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP.
* Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
* Folate: \<2.0 nanogram (ng) per millilitre (mL) (4.5 nanomole/liter \[L\]) (may rescreen in a minimum of 4 weeks).
* Ferritin: \<100 ng/mL (\<100 mcg/L).
* Transferrin saturation (TSAT): \<20 percent.

Answer: A