Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat tablets; Matching placebo tablets; Epoetin alfa vials; Saline vials or bags
Intervention description: Round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.; Matching placebo to daprodustat tablets supplied as round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.; Single-dose, preservative-free vials in unit dose strengths of 2000, 3000, 4000 and 10,000 Units/milliliter administered by the IV route.; 0.9% sodium chloride saline vials or bags administered by the IV route.
Intervention MeSH terms: Epoetin Alfa
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: This is a double-blind study, in which the subject, investigator, site staff and the sponsor will remain blinded to each subjects study treatment assignment throughout the course of the study, with the exception of a limited number of unblinded site staff who are necessary to maintain the blind, as well as a limited number of sponsor staff.
Enrollment: 407.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: CKD, EPO, rhEPO, Hemodialysis dependent, Daprodustat

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.
    

Eligibility criteria:

        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.