Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-in Incident Dialysis (ASCEND-ID)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat; Darbepoetin alfa; Iron therapy
Intervention description: Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 4, 6, 8, or 10 mg of daprodustat. Doses of 12, 16, and 24 mg of daprodustat will be provided using multiples of these tablet strengths.; Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 20, 30, 40, 60, 80, 100 and 150 mcg.; Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.
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: 312.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD

Summary:

      The purpose of this multi-center study is to evaluate the efficacy and safety of daprodustat
      in subjects with anemia associated with CKD.
    

Eligibility criteria:

        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.