Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Non-Dialysis (ASCEND-ND)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat; Darbepoetin alfa; Placebo; Iron Therapy
Intervention description: The initial dose or oral daprodustat for ESA naïve subjects is based on Hgb and for ESA users is based on prior ESA dose. The dose is adjusted thereafter in order to achieve the target range.; The initial dose of darbepoetin alfa to be administered for SC injection for ESA naïve subjects is based in Hgb and weight, and for ESA users is based on converting the prior ESA dose to the nearest available study darbepoetin alfa dose. The dose is adjusted thereafter in order to achieve the target range. IV darbepoetin alfa can be considered for participants transitioning to hemodialysis.; Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).; Participants will receive supplemental iron therapy if ferritin is <=100 ng/mL or TSAT is <=20%. The investigator will choose the route of administration and dose of iron.
Intervention MeSH terms: Darbepoetin alfa
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3872.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: GSK1278863; hemoglobin; anemia; non-dialysis; erythropoiesis stimulating agents; daprodustat; chronic kidney disease

Summary:

      The purpose of this multi-center event-driven study in non-dialysis (ND) participants with
      anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of
      daprodustat compared to darbepoetin alfa.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: 18 to 99 years of age (inclusive)

          -  CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5
             defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.

          -  Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use
             within the 6 weeks prior to screening and no ESA use between screening and
             randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks
             prior to screening and continuing between screening and randomization.

          -  For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to
             10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8
             should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.

          -  >=80% and <=120% compliance with placebo during run-in period.

          -  Informed consent (screening only): capable of giving signed informed consent which
             includes compliance with the requirements and restrictions.

        Exclusion Criteria:

          -  Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis
             within 90 days after study start (Day 1).

          -  Kidney transplant: Planned living-related or living-unrelated kidney transplant within
             52 weeks after study start (Day 1).

          -  Ferritin: <=100 nanograms (ng)/milliliter (mL) (<=100 micrograms/liter [L]) at
             screening.

          -  Transferrin saturation (TSAT) (screening only): <=20%.

          -  Aplasias: History of bone marrow aplasia or pure red cell aplasia.

          -  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 <=4 weeks prior to
             screening through to randomization (Day 1).

          -  MI or acute coronary syndrome: <=4 weeks prior to screening through to randomization
             (Day 1).

          -  Stroke or transient ischemic attack: <=4 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: Current uncontrolled hypertension as determined by
             the investigator.

          -  Bazett's corrected QT interval (QTcB) (Day 1): QTcB >500 millisecond (msec), or QTcB
             >530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for
             Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.

          -  Alanine transaminase (ALT): >2x upper limit of normal (ULN) at screening.

          -  Bilirubin: >1.5xULN at screening.

          -  Current unstable liver or biliary disease per investigator assessment, generally
             defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
             esophageal or gastric varices, persistent jaundice, or cirrhosis.

          -  Malignancy: 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 (example [e.g.] Bosniak Category II F, III or IV) > 3 centimeter (cm); with the
             exception of localized squamous cell or basal cell carcinoma of the skin that has been
             definitively treated >=4 weeks prior to screening.

          -  Severe allergic reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product, or darbepoetin alfa.

          -  Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g.,
             gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).

          -  Other study participation: 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).

          -  Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment
             duration of >30 days.

          -  Females only: Subject is pregnant [as confirmed by a positive urine human chorionic
             gonadotrophin (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.

          -  Other Conditions: 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 darbepoetin
             alfa) or prevent understanding of the aims or investigational procedures or possible
             consequences of the study.