Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Active-controlled, Double-blinded, Double-dummy, Parallel-group, Multicenter Study to Investigate the Efficacy and Safety of Oral Molidustat in Comparison to Darbepoetin Alfa in Dialysis Subjects Treated With Erythropoiesis-Stimulating Agents (ESAs)
Brief Summary: The purpose of this study is to evaluate the efficacy and safety of molidustat in comparison to darbepoetin alfa in dialysis subjects with renal anemia who are treated with Erythropoiesis-Stimulating Agents (ESAs).


Options:
A: 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
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:

1. Ages 18 to 75 years
2. Subject has voluntarily signed and dated an informed consent form (ICF), approved by an Ethics Committee (EC), after the nature of the study has been explained and the subject has had the opportunity to ask questions.
3. Diagnosis of chronic kidney disease, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4, or 5, not receiving dialysis; with an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
4. No use of an erythropoiesis-stimulating agent (ESA) for at least 5 weeks before randomization.
5. Mean of the two most recent Hb values during the Screening Period obtained at least 6 days apart must be ≥7.0 g/dL and \<10 g/dL.
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x upper limit of normal (ULN), and normal total bilirubin at screening visit (based on central laboratory results).
7. Body weight: 40 to 100 kg inclusive.
8. Subjects agreeing not to start taking any new Traditional Chinese Medicine (TCM) for anemia and not to change dose, schedule, or brand of any prescreening TCM for anemia from beginning of Screening Period through end of Follow-up Period without approval of the FibroGen China Medical Monitor.

Exclusion Criteria:

1. Any clinically significant infection or evidence of an active underlying infection.
2. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus antibody (anti-HCV Ab).
3. Chronic liver disease.
4. New York Heart Association Class III or IV congestive heart failure.
5. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event (eg, deep venous thrombosis or pulmonary embolism) within 52 weeks prior to Day 1.
6. Uncontrolled hypertension in the opinion of the investigator (eg, that requires change in anti-hypertensive medication within 2 weeks prior to randomization).
7. Diagnosis or suspicion (eg, complex kidney cyst of Bosniak Category II or higher) of renal cell carcinoma as shown on screening renal ultrasound.
8. History of malignancy except the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, or in situ cancer at any site.
9. Chronic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (eg, systemic lupus erythematosis \[SLE\], rheumatoid arthritis, celiac disease).
10. Clinically significant gastrointestinal bleeding.
11. Known history of myelodysplastic syndrome, multiple myeloma, hereditary hematologic disease such as thalassemia, sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD, hemosiderosis, hemochromatosis, known coagulation disorder, or hypercoagulable condition.
12. Any prior functioning organ transplant or a scheduled organ transplantation, or anephric.
13. Anticipated elective surgery that could lead to significant blood loss during the study period.
14. Anticipated use of dapsone or acetaminophen (paracetamol) \>2.0 g/day, or \>500 mg per dose repeated every 6 hours for more than 3 days.
15. Serum albumin \<2.5 g/dL.
16. Androgen, deferoxamine, deferiprone, or deferasirox therapy within 12 weeks prior to Day 1.
17. Life expectancy of \<12 months.
18. Blood transfusion within 12 weeks prior to Day 1 or anticipated need for transfusion.
19. IV iron supplement during the Screening Period and /or unwilling to withhold IV iron.
20. Immune suppressive or systematic steroid treatment within 12 weeks prior to Day 1.
21. History of alcohol or drug abuse within the past 2 years and inability to avoid consumption of more than \>3 alcoholic beverages per day.
22. Prior treatment with FG-4592 or any hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
23. Use of an investigational medication or treatment, participation in an investigational interventional study, or carryover effect of an investigational treatment expected during the study.
24. Women who are pregnant or breastfeeding.
25. Women of childbearing potential and men with sexual partners of child bearing potential who are not using adequate contraception.
26. Any medical condition that, in the opinion of the investigator, may pose a safety risk to a subject in this study, may confound efficacy or safety assessment, or may interfere with study participation.
D: 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

Answer: A