Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Open-label Study to Evaluate the Effect of Daprodustat on Blood Pressure in Subjects With Anemia Associated With Chronic Kidney Disease on Hemodialysis Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
Brief Summary: This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD) participants with anemia associated with chronic kidney disease (CKD), designed to compare the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA) washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1 and stratified by prior ESA dose before they undergo Acute Challenge 1, a single dose challenge to compare the acute effects on BP of the highest planned once-daily maintenance dose of daprodustat (24 milligrams \[mg\]) to the highest starting dose of epoetin alfa (100 units/kilogram \[U/kg\]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance period, where doses of either daprodustat or epoetin alfa will be administered and adjusted. At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated utilizing the same treatment dose administered in Acute Challenge 1; there will be a follow-up visit within 14+/-3 days after completing treatment.


Options:
A: Inclusion Criteria

* More than or equal to 40 years of age, at the time of signing the informed consent
* Stable Hgb 8.5 to 11.5 grams per deciliter (g/dL) inclusive.
* Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three-to five-times weekly for at least 4 weeks prior to screening.
* A single pool Kt/Vurea \>=1.2 based on a historical value obtained within 3 months prior to screening 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 should be at least 65 percent (%).
* Treated with an ESA (epoetins or their biosimilars, darbepoetin, or methoxy polyethylene glycol \[PEG\]-epoetin beta) for at least 4 weeks prior to screening.
* Participants may be on stable (\<=50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period) maintenance oral or intravenous (IV; \<=100 mg/week) iron supplementation. If participants are on oral or IV iron, then doses must be stable for the 4 weeks prior to Washout.
* Weight: Mid-week weight change between dialysis treatments \<5% as assessed post-dialysis at the Screening and Washout visits.
* On at least 1 antihypertensive medication (excluding diuretics) and on that same medication and the same dose for at least 1 week prior to Washout.
* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and the protocol.
* Willing and able to wear ABPM device for at least 25 hours on two separate sessions.

Exclusion Criteria

* Planned change from HD to peritoneal dialysis within the study time period, or on home dialysis.
* Planned for kidney transplant within the 16 weeks following the Screening visit.
* An epoetin alfa dose of \>=360 U/kg/week IV or \>=250 U/kg/week subcutaneous (SC), or darbepoetin dose of \>=1.8 micrograms (μg)/kg/week IV or SC, or methoxy PEG-epoetin beta dose of \>=2.2 μg/kg/week within the 8 weeks prior to screening through Week -4.
* Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) within the 4 weeks prior to the Washout.
* Occurrence of myocardial infarction or acute coronary syndrome within 3 months prior to Washout.
* Stroke or transient ischemic attack within 3 months prior to Washout.
* Chronic Class 4 heart failure, as defined by the New York Heart Association functional classification system diagnosed prior to Washout.
* QT interval corrected for heart rate using Bazett's formula (QTcB) \>500 milliseconds (msec), or QTcB \>530 msec in participants with Bundle Branch Block. There is no QTc exclusion for participants with a predominantly paced rhythm.
* Resting post dialysis SBP \>160 millimeters of mercury (mmHg); or DBP \>100 mmHg at screening or uncontrolled hypertension as determined by the investigator.
* Presence of atrial fibrillation.
* Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) diagnosed prior to Washout.
* History of bone marrow aplasia or pure red cell aplasia.
* Other causes of anemia including Pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
* Alanine transaminase (ALT) \>2 times upper limit of normal (ULN) (screening only) or Bilirubin \>1.5 times ULN (screening only) 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.
* Major surgery (excluding vascular access surgery) within the 3 months prior to Washout or planned during the study.
* Blood transfusion within the 8 weeks prior to Washout or an anticipated need for blood transfusion during the study.
* Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding within the 8 weeks prior to Washout.
* Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Washout.
* History of malignancy within the two years prior to screening through Day 1 or currently receiving treatment for cancer, or has a known complex kidney cyst (e.g., Bosniak Category IIF, III or IV) \>=3 centimeters.
* Participants with an upper arm diameter which cannot be measured by oscillometer/ sphygmomanometer cuff or for whom BP cannot be measured in the opposite arm of current vascular access.
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
* Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until Washout.
* The participant has participated in a clinical trial and has received an experimental investigational product within the 30 days prior to Day 1 or within 5 half lives of the investigational product prior to screening, whichever is longer.
* Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
* A female participant is pregnant (as confirmed by a positive serum human chorionic gonadotrophin test for females of reproductive potential only), participant is breastfeeding, or participant is of reproductive potential and does not agree to follow one of the pre-specified contraceptive options
* Vitamin B12 at or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks, following treatment).
* Folate at \<2.0 nanograms/milliliter (ng/mL) (4.5 Nanomoles per Liter) (may rescreen in a minimum of 4 weeks, following treatment).
* Ferritin at \<100 ng/mL
* Transferrin saturation at \<20%.
B: Inclusion Criteria:

* Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.
* Participants who are Stage 3, 4 or 5 CKD defined by estimated Glomerular Filtration Rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Hemoglobin as measured by HemoCue at screening visit and Day 1 is \<=11.0 grams/deciliter (g/dL) \[\<=110 gram/Litre (g/L)\].
* Palpable brachial artery as assessed at screening.
* Participants, if necessary may be on stable maintenance oral iron supplementation (\<50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period). If participants have been on intravenous (IV) iron, then participants will not have received IV iron for 4 weeks prior to the Day 1 visit.
* Male or female participants will be included.
* A female participant 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 has been on an approved form of contraceptive for the 4 weeks prior to Day 1 and agrees to follow the contraceptive guidance until the Follow-up visit.
* Capable of giving signed informed consent.

Exclusion Criteria:

* On dialysis or clinical evidence of impending need to initiate dialysis within 12 weeks of Day 1.
* Planned kidney transplant within 12 weeks of Day 1.
* Presence of an arteriovenous (AV) fistula.
* Recombinant human erythropoietin use within the 12 weeks prior to the screening visit and through Day 1.
* History of severe allergic or anaphylactic reactions or hypersensitivity to the study treatment or challenge agents, or excipients in the study treatments or challenge agents.
* Planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until all assessments on Day 42 have been successfully completed.
* The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or within 5 half-lives of the investigational product (whichever is longer) prior to screening and through Day 1.
* At or below the lower limit of the reference range at screening for Vitamin B12 (may rescreen in a minimum of 8 weeks).
* Ferritin \<=50 nanograms/milliliter \[\<=50 microgram/liter (µg/L)\] at screening.
* Transferrin saturation (TSAT) \<=15% (0.15) at screening.
* Folate \<2.0 nanogram/milliliter (4.5 nanomoles/liter; may rescreen in a minimum of 8 weeks) at screening.
* High sensitivity C-reactive protein (hs-CRP) \>=50 micrograms/milliliter (\>=50 mg/L) at screening.
* Myocardial infarction or acute coronary syndrome \<=12 weeks prior to screening and through Day 1.
* Hospitalization for greater than 24 hours \<=12 weeks prior to screening and through Day 1.
* Stroke or transient ischemic attack \<=12 weeks prior to screening and through Day 1.
* Class 4 heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
* Resting SBP \>180 millimeters of mercury (mmHg) or DBP \>110 mmHg at screening visit or current uncontrolled hypertension as determined by the investigator.
* QT interval corrected for heart rate using Bazett's formula (QTcB) \>500 milliseconds (msec), or QTcB \>530 msec in participants with bundle branch block. There is no corrected QT (QTc) exclusion for participants with a predominantly ventricular paced rhythm.
* Active chronic inflammatory disease that could impact erythropoiesis.
* History of bone marrow aplasia or pure red cell aplasia.
* Conditions, other than anemia of CKD, which can affect erythropoiesis.
* Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding from \<=8 weeks prior to screening and through Day 1.
* ALT \>2 times upper limit of normal (ULN; screening only).
* Bilirubin \>1.5 times ULN (screening only); Isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Major surgery within the 12 weeks prior to screening and through Day 1, or planned during the study.
* Anticipated or planned vascular access surgery (i.e., arteriovenous \[AV\] fistula) within the 12 weeks prior to screening and through the Day 42 assessments.
* Received a tissue heart valve replacement or repair within the 6 months prior to screening or has received a mechanical heart valve replacement.
* Blood transfusion within 6 weeks prior to screening and through Day 1, or an anticipated need for blood transfusion during the study.
* Clinical evidence of an acute infection, or history of infection requiring IV antibiotic therapy from 8 weeks prior to screening and through Day 1. Prophylactic oral antibiotics are allowed.
* History of malignancy within the two years prior to screening and through Day 1 or currently receiving treatment for cancer, with the exception of localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.
* Platelet count \<50,000/µL (\<50 Giga cells per liter).
* History of a bleeding disorder (e.g., hemophilia).
* Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
C: 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
D: 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

Answer: A