Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat (GSK1278863); Placebo; Iron therapy
Intervention description: Daprodustat will be available as 9 millimeter (mm) or 7 mm film-coated tablets. Daprodustat will be administered once daily via oral route and can be taken without regard to food.; Daprodustat matching placebo will be available as 9 mm or 7 mm film coated tablets. Placebo will be administered once daily via oral route and can be taken without regard to food.; Iron therapy will be administered if ferritin is <50 Nano gram per milliliter and/or TSAT is <15 percent.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized to receive Daprodustat or placebo in a randomized manner.
Masking: Double (Participant, Investigator)
Masking description: This will be a double-blind study. The participant, investigator, site staff, and study team will be blinded to the assigned study treatment.
Enrollment: 614.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non-Dialysis; Anemia; Chronic kidney disease; Recombinant human erythropoietin naïve; Hemoglobin; Daprodustat

Summary:

      The purpose of this multi-center study in non-dialysis participants with anemia associated
      with CKD is to evaluate safety, efficacy and quality of life of daprodustat compared to
      placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          -  >=18 years of age at the time of signing the informed consent.

          -  Have CKD, confirmed at screening: Kidney Disease Outcomes Quality Initiative (KDOQI)
             CKD stages 3, 4, or 5 defined by Estimated glomerular filtration rate (eGFR) using the
             CKD Epidemiology Collaboration (CKD-EPI) formula.

          -  Participants with Stable HemoCue Hgb from 8.5 to 10.5 at screening visit (Week -4) and
             from 8.5 to 10.0 g/dL at randomization (Day 1).

          -  Participants may receive up to one intravenous (IV) iron dose within the 8 weeks prior
             to screening and NO IV iron use between screening visit and randomization (Day 1).

          -  If needed, participant may be on stable maintenance oral iron supplementation. There
             should be <50% change in overall dose and no change in type of iron prescribed in the
             4 weeks prior to Day 1 randomization visit.

          -  Male and female participants are eligible. 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 WOCBP
             who agrees to follow the contraceptive guidance during the treatment period and for at
             least 4 weeks after the last dose of study treatment.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  Participants who are on dialysis or clinical evidence of impending need to initiate
             dialysis within 180 days after randomization (Day 1).

          -  Planned living-related or living-unrelated kidney transplant within 28 weeks after
             randomization (Day 1).

          -  Transferrin saturation (TSAT) <15 percent (Screening only).

          -  Ferritin <50 nanograms per milliliter (ng/mL) (Screening only).

          -  History of rhEPO or rhEPO analogue use within the 8 weeks prior to screening and rhEPO
             use between screening and randomization (Day 1).

          -  History of transfusion within the 8 weeks prior to screening and transfusion between
             screening and randomization (Day 1).

          -  History of bone marrow aplasia or pure red cell aplasia (PRCA).

          -  Participants with Megaloblastic anemia (untreated pernicious anemia and folate
             deficiency), thalassemia major, sickle cell disease or myelodysplastic syndrome.

          -  Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or
             clinically significant gastrointestinal (GI) bleeding <= 8 weeks prior to screening
             through to randomization (Day 1).

          -  History of severe allergic or anaphylactic reactions or hypersensitivity to excipients
             in the investigational product.

          -  Use of strong inhibitor of CYP2C8 (for example, gemfibrozil) or strong inducers of
             CYP2C8 (for example, rifampin/rifampicin).

          -  Ferric citrate use within 4 weeks prior to randomization (Day 1).

          -  Use of other investigational agent or device prior to screening through to
             randomization (Day 1).

          -  Any prior treatment with daprodustat for a treatment duration of >30 days.

          -  MI or acute coronary syndrome within the 8 weeks prior to screening through to
             randomization. (Day 1).

          -  Stroke or transient ischemic attack within the 8 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.

          -  QT interval corrected by Bazett's formula (QTcB) >500 milliseconds (msec) or QTcB >530
             msec in participants with bundle branch block. There is no corrected QT interval (QTc)
             exclusion for participants with a predominantly paced rhythm.

          -  Alanine transaminase (ALT) >2x upper limit of normal (ULN) at screening (Week -4).

          -  Bilirubin >1.5xULN at screening (Week -4).

          -  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.

          -  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 (for
             example, Bosniak Category II F, III or IV) > 3 centimeters (cm).

          -  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.

          -  Current uncontrolled hypertension as determined by the investigator.