Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Four-week, Phase IIa, Randomized, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Switching Subjects From a Stable Dose of Recombinant Human Erythropoietin to GSK1278863 in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease
Brief Summary: This is a four-week, Phase IIa, randomized, active-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of switching subjects from stable rhEPO to GSK1278863 in approximately 68 hemodialysis-dependent subjects with anemia associated with chronic kidney disease. The study consists of a screening phase of 2 weeks, a 4-week treatment phase and a 2-week follow-up phase. The range of Hgb values for study eligibility is 9.5-12.0 g/dL and the subjects must have received the same rhEPO product with total weekly doses that varied by no more than 50% during the 4 weeks prior to the Screening visit (Week -1. This study aims to estimate the relationship between dose of GSK1278863 and Hgb response in hemodialysis-dependent (HDD) subjects with anemia associated with chronic kidney disease after switching from a stable maintenance dose of recombinant human erythropoetin (rhEPO).


Options:
A: 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.
B: Inclusion Criteria:

1. CKD with end-stage renal disease (ESRD) on either hemodialysis (HD) or peritoneal dialysis (PD)

Exclusion Criteria:

1. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus antibody (anti-HCV Ab).
2. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event (for example, deep venous thrombosis or pulmonary embolism) within 26 weeks prior to Day 1.
3. History of malignancy, myelodysplastic syndrome, and multiple myeloma.
4. Chronic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (for example, systemic lupus erythematosis \[SLE\], rheumatoid arthritis, celiac disease).
5. Clinically significant gastrointestinal bleeding.
6. Women of childbearing potential and men with sexual partners of child bearing potential who are not using adequate contraception.
C: Inclusion Criteria:

* Subjects with renal anemia who have been receiving recombinant human erythropoietin (rHuEPO, two times weekly or three times weekly) or darbepoetin alfa (intravenous treatment) within the doses approved in Japan for more than 8 weeks before the screening assessment
* Mean of the subject's two most recent Hb values before dialysis after the longest dialysis interval during the Screening Period must be ≥10.0 g/dL and ≤12.0 g/dL
* Either transferrin saturation (TSAT) ≥ 20% or serum ferritin ≥ 100 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 untreated and macular edema untreated
* 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
* History of pure red cell aplasia
* 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) and/or ophthalmological surgery 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
D: Inclusion Criteria:

1. Age and weight: \>/=18 years of age and \>/=45 kg (weight post-dialysis).
2. On three times weekly hemodialysis for at least 8 weeks, irrespective of eGFR values and stage of chronic kidney disease (CKD).
3. A single-pool Kt/Vurea of \>/=1.2 based on a historical value obtained within the prior month 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%.
4. rhEPO use: Using the same rhEPO (epoetins or darbepoetin) with total weekly doses that varied by no more than 50% during the prior 4 weeks (i.e., maximum vs. minimum total weekly doses \</=50%).
5. Hgb concentrations 9.5-12.0 g/dL (inclusive).
6. Vitamin B12 above the lower limit of the reference range (may rescreen in two months).
7. Folate: \>/= 2.0 ng/mL (may rescreen in one month).
8. Ferritin: \>/=40 ng/mL with the absence of microcytic or hypochromic RBCs.
9. Transferrin saturation (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 one of the 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 \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)\>40MIU/ml and estradiol \<40pg/ml is confirmatory\]. 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 enrolment. For most forms 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 one of the approved contraceptive methods from the time of Screening until completion of the Follow-up Visit.

Exclusion Criteria:

1. Dialysis modality: On peritoneal dialysis OR planned change in dialysis modality within the study time period.
2. rhEPO Hyporesponders: As defined by an epoetin dose of \>/=360 IU/kg/week IV or darbepoetin dose of \>/=1.8 µg/kg/week IV within the prior 8 weeks.
3. Renal transplant: Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.
4. Mircera or Peginesatide: Current or prior use (within the prior 8 weeks) of Mircera (methoxy polyethylene glycol epoetin beta) OR peginesatide.
5. Total CPK: \>5x the upper limit of the reference range.
6. HIV: Positive HIV antibody.
7. History of myocardial infarction or acute coronary syndrome within the prior 6 months.
8. History of stroke or transient ischemic attacks (TIAs) within the prior 6 months.
9. Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
10. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment, is defined as follows:

    * DBP \>100 mmHg or SBP\>160 mmHg for subjects taking hypertension medication(s) before screening and dialysis, if required.
    * DBP \>105 mmHg or SBP\>170 mmHg for subjects who are asked to hold hypertension medication(s) before screening and dialysis.
11. 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 except shunt thrombosis) within the prior 6 months.
12. 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).
13. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
14. Haematological disease: Any haematological 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, haematological malignancy, myeloma, haemolytic anemia) or any other cause of anemia other than renal disease.
15. 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 \[alkaline phosphatase, alanine transaminase (ALT) or aspartate transaminase (AST) \> 2.0 x upper limit of normal (ULN) or total bilirubin \> 1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
16. Major surgery: (excluding vascular access surgery) Within the prior 12 weeks or planned during the study.
17. Transfusion: Blood transfusion within the prior 12 weeks or an anticipated need for blood transfusion during the study.
18. Ulcer and Active GI Bleeding: Evidence of active peptic, duodenal, or esophageal ulcer disease OR GI bleeding within the prior 12 weeks.
19. 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).
20. Malignancy: History of malignancy within the prior 5 years 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.
21. Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months or macular edema requiring treatment.
22. Severe reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
23. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Screening until the Follow-up Visit.
24. Androgens: New androgen therapy or changes to pre-existing androgen regimen within the prior 12 weeks.
25. Prior investigational product exposure: The Subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days.
26. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
27. Other Conditions: Any condition which in the investigator's opinion should exclude the subject from participating in the study.
28. Pregnancy or Lactation: Pregnant females as determined by positive serum hCG test OR women who are lactating at Screening or during the trial.

Answer: D