Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Four-week Phase IIa, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Taking Recombinant Human Erythropoietin and Are Not Undergoing Dialysis
Brief Summary: This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in approximately 68 subjects with anemia associated with chronic kidney disease who are not taking rhEPO and are not undergoing dialysis. The range of Hgb values for study eligibility is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion.


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:

1. Age and weight: \>/= 18 years of age and \>/= 45 kg.
2. Not routinely undergoing dialysis, regardless of the modality (either hemodialysis or peritoneal dialysis) or dialysis planned during the time the subject would be enrolled in the study.
3. No current or prior rhEPO use within the past 7 weeks; e.g., epoetins (or their biosimilars), darbepoetin, Mircera (methoxy polyethylene glycol epoetin beta), peginesatide or their biosimilars..
4. KDOQI CKD stages 3/4/5 defined by eGFR using the Modification of Diet for Renal Disease (MDRD).
5. Hgb: Hgb concentrations 8.5-11.0 g/dL (inclusive) as outlined in Section 4.2.
6. Vitamin B12: Above the lower limit of the reference range (may rescreen in 2 months).
7. Folate: \>/=2.0 ng/mL at Screening. May rescreen in a month.
8. Ferritin: \>/=40 ng/mL with the absence of microcytic or hypochromic RBCs.
9. TSAT within the reference range.
10. Iron replacement therapy: Stable maintenance dose of oral iron replacement therapy, if required, that will be maintained throughout the study. NOTE: IV iron replacement therapy is not allowed the two weeks prior to Screening through the end of the study (Week 6).
11. QTc: QTcB \<470 msec or QTcB \<480 msec in subjects with bundle branch block obtained at Screening Visit, based on Central Reader's interpretation.
12. Females: Eligible to participate if she is of childbearing potential, and must agree to use 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 of hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)\>40 MIU/ml and estradiol \<40 pg/ml is confirmatory\]. 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 enrollment. For most types of HRT, at least 2 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
13. Males: Must agree to use approved contraceptive methods from the time of Screening until completion of the Follow-up Visit.

Exclusion Criteria:

1. Dialysis: Planning to initiate dialysis during the study or who have a high potential for initiating dialysis during study participation.
2. Renal transplant: Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.
3. Total CPK: \>5x the upper limit of the reference range.
4. HIV: Positive HIV antibody.
5. History of myocardial infarction or acute coronary syndrome within the prior 6 months.
6. History of stroke or TIAs.
7. Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
8. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment, defined as DBP \>100 mmHg or SBP\>160 mmHg.
9. 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), or other thrombosis related condition) within the prior 6 months.
10. Pulmonary hypertension: Known pulmonary hypertension and those at higher risk (than normally associated with CKD) for pre-existing elevation in pulmonary pressure (e.g., significant heart failure or lung disease requiring supplemental oxygen, or those with connective tissue diseases).
11. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
12. Hematological disease: Any hematological disease including those affecting platelets, the coagulation disorders (e.g., Protein C or S deficiency) or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia) or any other cause of anemia other than renal disease.
13. 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 \[alkaline phosphatase, ALT or AST \> 2.0 x upper limit of normal (ULN) or total bilirubin \> 1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
14. Major surgery: Within the prior 12 weeks or planned during the study.
15. Transfusion: Blood transfusion within the prior 12 weeks or an anticipated need for blood transfusion during the study.
16. Ulcer and Active GI Bleeding: Evidence of active peptic, duodenal, or esophageal ulcer disease or active GI bleeding within the prior 12 weeks.
17. Acute infection: Clinical evidence of acute infection or history of infection requiring intravenous (IV) antibiotic therapy the eight weeks prior to Screening through Day 1 (randomization).
18. Malignancy: History of malignancy within 5 years of Screening or are receiving treatment for cancer or those with 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.
19. Hyperparathyroidism: Clinically significant hyperparathyroidism in the opinion of the Investigator, including subjects with parathyroid hormone (PTH) values ≥600 pg/mL.
20. Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months, or macular edema requiring treatment.
21. Severe reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
22. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Screening until the Follow-up Visit.
23. Androgens: New androgen therapy or changes to pre-existing androgen regimen within prior 12 weeks.
24. Prior investigational product exposure: The subject has participated in a clinical trial and has received an experimental investigational product within prior 30 days.
25. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
26. Other conditions: Any condition which in the investigators opinion should exclude the subject from participating in the study.
27. Pregnancy and lactation: Pregnant females as determined by positive urine hCG test, OR women who are lactating at Screening or during the trial.
C: Inclusion Criteria:

* Subject with ESKD (end-stage kidney disease) on regular dialysis (including, hemodiafiltration, hemofiltration, hemodialysis, and other modalities except for peritoneal dialysis) weekly or more than weekly for at least 12 weeks prior to randomization
* Body weight (after dialysis) \> 40 and ≤ 160 kg at screening
* Male or female subject ≥ 20 years of age at screening
* At least one kidney
* Treated with weekly or bi-weekly dose of darbepoetin alfa, monthly or bi-weekly dose of epoetin beta pegol, OR weekly, biweekly, twice or three times per week dose of epoetin alfa/beta, and having had no more than one dose change within 8 weeks prior to randomization
* Mean screening Hb level ≥ 9.5 and \< 12.0 g/dL (mean of all central laboratory Hb levels before dialysis \[at least 2 measurements must be taken ≥ 2 days apart\] during the screening period, AND all Hb level must be measured by the central laboratory, AND the difference between the lowest level and highest level is \< 1.2 g/dL), with the last screening Hb level measurement within 14 days prior to randomization
* Ferritin ≥ 100 ng/mL or transferrin saturation ≥ 20% at screening
* Serum folate level and serum vitamin B12 level above lower limit of normal (LLN) at screening

Exclusion Criteria:

* New York Heart Association (NYHA) Class III or IV congestive heart failure
* History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, pulmonary thromboembolism, and acute limb ischemia) within 6 months prior to randomization
* Sustained, poorly controlled arterial hypertension (defined as systolic BP (blood pressure) ≥ 180mmHg or diastolic BP ≥ 110mmHg) or hypotension (defined as systolic BP \< 90mmHg) at randomization
* Proliferative choroidal or retinal disease, such as neovascular agerelated macular degeneration or proliferative diabetic retinopathy requiring invasive treatment (e.g., intraocular injections or laser photocoagulation) at screening
D: Inclusion Criteria:

* Receiving chronic, outpatient three times weekly (TIW) in-center hemodialysis for end-stage renal disease for at least 12 weeks prior to 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
* Use of any approved erythropoiesis-stimulating agents (ESAs) for at least the 8 weeks prior to Screening Visit 2
* Two hemoglobin (Hb) values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges:

  1. Hb values between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the United States;
  2. Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe
* 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

Exclusion Criteria:

* Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product (IMP). If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, or birth control.
* 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
* Women who are breast feeding and/or who have a positive pregnancy test result prior to receiving IMP
* Participants with contraindication to required trial assessment
* Participants who, is in opinion of the investigator or medical monitor, have a medical history or medical findings inconsistent with safety or trial compliance
* 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)
* Participants meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2

  1. Methoxy polyethylene glycol-epoetin beta \> 50 micrograms (µg)/week;
  2. Darbepoetin alfa \> 100 µg/week;
  3. Epoetin analogues \> 23000 International Units (IU)/week
* Active bleeding or recent blood loss within 8 weeks prior to randomization
* Red blood cell transfusion within 8 weeks prior to randomization
* Anticipated to discontinue hemodialysis during the trial
* Judged by the investigator that the participant is likely to need rescue therapy (ESA administration or red blood cell \[RBC\] transfusion) immediately after enrollment in the trial
* 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 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 an ESA
* 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 a new or recurrent episode 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 subjects 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, darbepoetin alfa, or any of their excipients
* Use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to screening or during screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase inhibitor. Participants may participate in another concurrent trial only if that trial is a non-interventional, observational investigation.
* Participants with bilateral native nephrectomy
* Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration
* Any other reason, which in the opinion of the investigator, would make the participant not suitable for participation in the trial

Answer: B