Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Multi-center, Randomized, 2-arm, Open-label Study of Intermittent Oral Dosing of ASP1517 in Erythropoiesis Stimulating Agent-naive Hemodialysis Chronic Kidney Disease Patients With Anemia
Brief Summary: The objective of this study is to evaluate the safety and efficacy of ASP1517 in ESA-naive hemodialysis chronic kidney disease patients with anemia.


Options:
A: Inclusion Criteria

* Age (informed consent): \>=20 years of age
* Dialysis: On HD or hemodiafiltration (HDF) given three times weekly for at least 12 weeks prior to screening
* ESAs: Use of one and the same ESA for 10 weeks prior to screening
* ESA dose: Darbepoetin alfa 10 to 60 μg per week, epoetin (including biosimilars) \<=9000 international units (IU) per week, or epoetin beta pegol \<=250 μg per 4 weeks
* Hgb:\>=9.5 g/dL and \<=12.5 g/dL. Determined at the site using an Hgb analyzer
* Iron parameters: Ferritin \>100 nanogram (ng)/millilitre (mL) or transferrin saturation (TSAT) \>20 percent (screening verification only)
* Gender (screening verification only): Female or male

Females: Not pregnant \[demonstrated to be negative for human chorionic gonadotropin (hCG) in serum\], not breast-feeding, and meet at least one of the following:

• Females of non-childbearing potential are defined as follows:

Pre-menopausal with at least one of the following and no plans to utilise assisted reproductive techniques (e.g., in vitro fertilisation 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 A) females 60 years of age or older or B) In females \< 60 years of age, 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is confirmatory (see separately specified reference ranges)\]. 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.

  • Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in "GlaxoSmithKline (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.
* 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.

Exclusion Criteria

CKD-related criteria

* 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 10 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 10 weeks prior to screening or during a period from screening to Day 1
* Heart failure: Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system
* Corrected QT (QTc) Interval (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):

  * Alanine transaminase (ALT) \>2 upper limit of normal (ULN)
  * Bilirubin \>1.5×ULN (isolated bilirubin \>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35 percent)
  * Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis)
* Malignancy: History of malignancy within 2 years prior to screening, currently receiving treatment for cancer, or complex kidney cyst \>3 centimeters (cm) (II F, III or IV based on the Bosniak classification)

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
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
* Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited during the study period \[prohibited medications: strong inducers and inhibitor of Cytochrome P450 (CYP) 2C8\].
* 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 daprodustat: Any prior treatment with daprodustat 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:

* 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: 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
D: Key Inclusion Criteria:

* 18 to 82 years of age, inclusive
* Chronic Kidney Disease with a GFR category of G3a-G5 and not yet on dialysis
* eGFR ≥ 10 and ≤ 65 mL/minute/1.73 m2
* Anemia secondary to CKD with an ESA status and a Screening HGB as per protocol
* Iron replete with ferritin and TSAT levels as defined per protocol

Key Exclusion Criteria:

* BMI \> 44.0 kg/m2
* Red blood cell transfusion within 11 weeks prior to the Screening visit
* Androgen therapy within the previous 21 days prior to the Screening visit
* Intravenous iron within the past 4 weeks prior to the Screening visit
* AST or ALT \>1.8x ULN, alkaline phosphatase \>2x ULN, or total bilirubin \>1.5x ULN
* Screening ECG with QTc \> 500 msec
* Uncontrolled hypertension
* Class III or IV congestive heart failure
* Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to the Screening visit

Answer: B