Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study in Hemodialysis Participants With Anemia of Chronic Kidney Disease to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Recombinant Human Erythropoietin or Its Analogs
Brief Summary: This Phase 3 study in hemodialysis-dependent subjects with anemia will evaluate the efficacy and safety of daprodustat administered three-times weekly compared to epoetin alfa, the current standard of care. This study includes a 4 week Screening Period, a 52 week Treatment Period and a 4 to 6 week follow-up period. Each subject will remain in the study for up to 62 weeks. Approximately 402 subjects will be randomized to receive either daprodustat three times weekly or epoetin alfa three-times weekly or once weekly, depending on dose level.


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:

* 18 to 99 years of age inclusive.
* Planning to start chronic dialysis within the next 6 weeks (from the date of the screening visit) OR have started and received dialysis (as specified below) for end-stage renal disease for a maximum of \<=90 days immediately prior to randomization and is not expected to stop dialysis during the duration of the trial: HD \>=2 times per week or PD \>=4 times per week including incremental schedule; subjects on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) are eligible.
* Hemoglobin concentration as measured by HemoCue (range inclusive): 8 to 10.5 g/dL (5-6.5 millimoles per liter \[mmol/L\]) at screening and 8-11.0 g/dL (5 to 6.8 mmol/L) at randomization.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

* Planned living-related or living-unrelated kidney transplant during the study.
* Ferritin: \<=100 nanograms per milliliter (ng/mL) (\<=100 micrograms per liter \[mcg/L\]) at screening or after IV iron supplementation.
* Transferrin saturation (TSAT): \<=20% at screening or after IV iron supplementation.
* Vitamin B12 (cobalamin): Below the lower limit of the reference range at screening or after vitamin B12 supplementation.
* Folate: \<2.0 ng/mL (\<4.5 nanomoles per liter \[nmol/L\]) at screening.
* Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA).
* 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 \<=10 weeks prior to screening through to randomization (Day 1).
* Use of any Erythropoiesis-stimulating agent (ESA) treatment within 8 weeks prior to screening except for limited use as part of dialysis initiation. Note : Limited use is defined as no more than 6 weeks of short acting ESA (rhEPO or biosimilars; maximum of 20000 unit total) or long acting ESA (darbepoetin alfa \[maximum of 100 mcg total\] or methoxy polyethylene glycol-epoetin beta \[maximum of 125 mcg total\]) received before or after starting dialysis.
* Myocardial infarction or acute coronary syndrome: \<=10 weeks prior to screening through to randomization (Day 1).
* Stroke or transient ischemic attack: \<=10 weeks prior to screening through to randomization (Day 1).
* Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
* Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of rhEPO.
* QT correction using Bazett's (QTcB) (Day 1): QTcB \>500 milliseconds (msec), or QTcB \>530 msec in subjects with bundle branch block. There is no QTc exclusion for subjects with a predominantly ventricular paced rhythm.
* Liver disease (any one of the following): 1. Alanine transaminase (ALT) \>2 times upper limit of normal (ULN) (screening only). 2. Bilirubin \>1.5 times ULN (screening only) (NOTE: Isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). 3. Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic hepatitis B or C, or Gilbert's syndrome) are acceptable if subject otherwise meets entry criteria.
* 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 (i.e. Bosniak Category II F, III or IV) \>3 centimeter (cm). The only exception is localized squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=10 weeks prior to screening.
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product or to darbepoetin alfa.
* Use of strong Cytochrome P4502C8 (CYP2C8) inhibitors (example gemfibrozil) or strong CYP2C8 inducers (example rifampin/rifampicin).
* 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).
* Any prior treatment with daprodustat for treatment duration of \>30 days.
* Females only: Subject is pregnant \[as confirmed by a positive serum human chorionic gonadotropin (hCG) test for females of reproductive potential (FRP) only\], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options in the List of Highly Effective Methods for Avoiding Pregnancy.
* 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 (example intolerance to rhEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study.
C: Inclusion Criteria:

* - Eligible subjects will have a diagnosis of anemia associated with CKD(chronic kidney disease).
* Women without childbearing potential
* Male or female subject ≥ 18 years of age with anemia of CKD at screening
* On dialysis, defined as regular long-term hemodialysis, with the same modality of dialysis for ≥ 3 months before randomization
* Dialysis vascular access via native arteriovenous fistula, synthetic graft, long-term catheters, or long-term tunneled catheters
* Treated with epoetin alfa (US or Japan) or epoetin beta (Japan) via intravenous (IV) or subcutaneous (SC) route, on stable dosing defined as a \< 50% change from the maximum prescribed weekly dose with no change in the prescribed frequency during the last 8 weeks prior to randomization
* At least one kidney
* Mean screening Hb concentration 9.0 to 11.5 g/dL inclusive (mean of all local laboratory Hb measurements \[at least 2 measurements must be taken ≥ 2 days apart\] during the 4 week screening period, AND none of the measurements can be \< 9.0 g/dL or \> 12.0 g /dL
* Serum ferritin levels ≥ 100 μg/L OR transferrin saturation ≥ 20% at screening. Iron substitution is allowed
* Folate and vitamin B12 levels above the lower limit of normal. Supplementation is allowed
* Exclusion Criteria:
* Subjects with significant acute or chronic bleeding, such as overt gastrointestinal bleeding
* Hereditary hemoglobinopathies (including, but not limited to, sickle cell disease, beta thalassemia, and thalassemia major) which may be the primary cause of anemia
* Chronic lymphoproliferative diseases
* Any allograft (including renal allograft) in place and on immunosuppressive therapy, or a scheduled kidney transplant within the next 16 weeks (being on a waiting list does not exclude the subject)
* Chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease)
* Subjects treated with immuno- or myelosuppressive therapy within 8 weeks prior to randomization: e.g., everolimus, sirolimus, rituximab, azathioprine, mycophenolate mofetil, mycophenolic acid, cyclosporine,methotrexate, and tacrolimus, chemotherapeutic agents and other anticancer agents, and systemic steroids (except inhaled steroids) for 7 days
* RBC-containing transfusion within 8 weeks before randomization
* History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within the last 6 months from the initial screening visit
* Sustained, poorly controlled arterial hypertension or hypotension at screening, defined as a mean BP ≥ 180/110 mmHg or systolic BP \< 95 mmHg, respectively
* Severe rhythm or conduction disorder (e.g., HR \< 50 or \> 110 bpm, atrial flutter, prolonged QT \>500 msec, second or third degree atrioventricular \[AV\]block if not treated with a pacemaker)
* New York Heart Association Class III or IV congestive heart failure
* Severe hepatic insufficiency (defined as alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or gamma-glutamyl transferase \> 3 times the upper limit of normal \[ULN\], total bilirubin \> 2 mg/dL, or Child-Pugh B or C) or active hepatitis in the investigator's opinion
* A scheduled surgery that may be expected to lead to significant blood loss
D: Inclusion Criteria:

* Subject must be 18 to 99 years of age inclusive, at the time of signing the informed consent.
* Use of any approved rhEPO or analog for at least 8 weeks prior to the screening visit and continuing during the screening period until randomization (Day 1).
* Hgb concentration (measured by HemoCue) within the following range: Week -4: Hgb 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). If Hgb is 11.6 to 11.9 grams/deciliter (7.2 to 7.4 millimoles/liter), up to two retests are allowed; the retest value must be between 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). Day 1: Hgb 8 to 11 grams/deciliter (5 to 6.8 millimoles/liter) and receiving at least the minimum rhEPO or analog dose 3. Hgb\>11 to 11.5 grams/deciliter (6.8 to 7.1 millimoles/liter) and receiving greater than the minimum rhEPO or analog dose 3.
* On hemodialysis (including hemofiltration or hemodiafiltration) \>90 days prior to screening and continuing during the screening period.
* On hemodialysis (in-center) \>=3 times per week.
* Male and female subjects are eligible. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP), or A WOCBP who agrees to follow the contraceptive guidance from at least 28 days prior to first dose of study treatment and for at least 28 days after the last dose of study treatment.
* Capable of giving signed informed consent.
* In France, a subject will be eligible for inclusion in this study if he or she is either affiliated to or beneficiary of a social security category.

Exclusion Criteria:

* Planned living-related or living-unrelated kidney transplant within 52 weeks after randomization (Day 1).
* Ferritin: \<=100 nanograms/milliliter (\<=100 micrograms/liter), at screening.
* Transferrin saturation (TSAT): \<=20 percent, at screening. If TSAT is 18 to 20 percent, then a retest using a new blood sample can be obtained within 7 days of the final laboratory report; the final retest value must be \>20 percent to confirm eligibility.
* Aplasias: History of bone marrow aplasia or pure red cell aplasia.
* Conditions, other than anemia of CKD, which can affect erythropoiesis.
* Myocardial infarction (MI) or acute coronary syndrome within 8 weeks prior to screening through to randomization (Day 1).
* Stroke or transient ischemic attack within 8 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 as determined by the investigator that would contraindicate the use of rhEPO.
* Bazett's correction of QTc interval (QTcB): at Day 1: QTcB \>500 milliseconds, or QTcB \>530 milliseconds in subjects with bundle branch block. There is no QTc (corrected QT) exclusion for subjects with a predominantly ventricular paced rhythm.
* Liver Disease: presence of any one of the following liver-related laboratory values or conditions, at screening, is exclusionary: ALT \>2x upper limit of normal (ULN); Bilirubin \>1.5x ULN; or Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
* Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant gastro intestinal bleeding \<= 8 weeks prior to screening through to randomization (Day 1).
* History of malignancy within 2 years prior to screening through to randomization (Day 1), currently receiving treatment for cancer, or complex kidney cyst (e.g., Bosniak Category IIF, III or IV) \>3 centimeters.
* Use of a strong inhibitor of Cytochrome P4502C8 \[CYP2C8\] (e.g. gemfibrozil) or a strong inducer of CYP2C8 (e.g. rifampin/rifampicin).
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (daprodustat) or epoetin alfa.
* Use of another investigational agent within 30 days or within five half-lives of the investigational agent (whichever is longer) or currently participating in a study of an investigational device prior to screening through to randomization (Day 1).
* Any prior treatment with daprodustat for treatment duration of \>30 days.
* 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 rhEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Answer: D