Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Sequential Group, Dose Ranging Safety and Efficacy Study of FG 4592 in Non-dialysis Chronic Kidney Disease (CKD) Subjects With Anemia
Brief Summary: The primary purpose of this study is to evaluate efficacy and safety of FG-4592 in the correction of anemia in non-dialysis chronic kidney disease patients.


Options:
A: Inclusion Criteria:

1. Age 18 to 75 years
2. Subject has voluntarily signed and dated an informed consent form
3. Chronic Kidney Disease, not receiving dialysis
4. Hemoglobin (Hb) values in 4 screening visits and the mean Hb must be \<10g/dL
5. Aminotransferase levels (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\]) and total bilirubin must be ≤ upper limit of normal (ULN) during the screening period
6. Serum alkaline phosphatase (ALP) ≤2x ULN during screening period. Subjects with serum ALP values between 1 x and 2 x ULN may be included only if bone-specific ALP (BSAP) is also elevated \> ULN
7. Total bilirubin values must be ≤ULN during screening period
8. Serum folate and vitamin B12 levels above the lower limit of normal (LLN)
9. Body weight: 40 to 100 kg (dry weight) inclusive
10. Body mass index (BMI): 16 to 38 kg/m2 inclusive

Exclusion Criteria:

1. Received any erythropoiesis-stimulating agent (ESA) other than epoetin alfa within 12 weeks prior to Day 1
2. Any clinically significant infection or evidence of an underlying infection such as a white blood cell count (WBC) \> ULN during screening on two separate occasions,
3. Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); anti-hepatitis C virus antibody (anti-HCV Ab)
4. History of chronic liver disease
5. New York Heart Association Class III or IV congestive heart failure
6. Chronic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
7. Active or chronic gastrointestinal bleeding, or a known coagulation disorder
8. Hemoglobinopathy (e.g., homozygous sickle-cell disease, thalassemia of all types, etc.)
9. Hematological disorders, including myelodysplastic syndrome, multiple myeloma, or pure red cell aplasia
10. History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
11. Active hemolysis or diagnosis of hemolytic syndrome
12. Known bone marrow fibrosis
13. Uncontrolled or symptomatic secondary hyperparathyroidism (PTH\>600ng/L)
14. Any prior organ transplantation
15. Drug-treated gastroparesis, short-bowel syndrome, or any other gastrointestinal condition that may lead to reduced absorption of study drug
16. Serum albumin \<3 g/dL
17. History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the subject
18. Prior treatment with FG-4592
19. Use of an investigational medication or treatment, or carryover effect of an investigational treatment expected, during the screening visit, treatment and follow-up period.
20. Use of traditional Chinese medicines (TCM) during the screening visit to Day 1 or plans to use TCM during the study unless approved in advance by the Medical Monitor
B: Inclusion Criteria:

* Age: 18 to 99 years of age (inclusive)
* CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization.
* For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.
* \>=80% and \<=120% compliance with placebo during run-in period.
* Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions.

Exclusion Criteria:

* Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
* Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
* Ferritin: \<=100 nanograms (ng)/milliliter (mL) (\<=100 micrograms/liter \[L\]) at screening.
* Transferrin saturation (TSAT) (screening only): \<=20%.
* Aplasias: History of bone marrow aplasia or pure red cell aplasia.
* Other causes of anemia: untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
* Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant GI bleeding \<=4 weeks prior to screening through to randomization (Day 1).
* MI or acute coronary syndrome: \<=4 weeks prior to screening through to randomization (Day 1).
* Stroke or transient ischemic attack: \<=4 weeks prior to screening through to randomization (Day 1).
* Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
* Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator.
* Bazett's corrected QT interval (QTcB) (Day 1): QTcB \>500 millisecond (msec), or QTcB \>530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.
* Alanine transaminase (ALT): \>2x upper limit of normal (ULN) at screening.
* Bilirubin: \>1.5xULN at screening.
* Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
* Malignancy: History of malignancy within the 2 years prior to screening through to randomization (Day 1) or currently receiving treatment for cancer, or complex kidney cyst (example \[e.g.\] Bosniak Category II F, III or IV) \> 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=4 weeks prior to screening.
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or darbepoetin alfa.
* Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
* Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
* Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of \>30 days.
* Females only: Subject is pregnant \[as confirmed by a positive urine human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only\], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options.
* 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 (e.g., intolerance to darbepoetin alfa) or prevent understanding of the aims or investigational procedures or possible consequences of the study.
C: 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.
D: 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

Answer: A