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A 52-week Open-label (Sponsor-blind), Randomized, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Efficacy and Safety of Daprodustat Compared to Recombinant Human Erythropoietin in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Initiating Dialysis (NCT03029208)

The study will evaluate the safety and efficacy of daprodustat compared to rhEPO for treatment of anemia associated with CKD in subjects who are starting dialysis or who have recently started dialysis. Previous trial in dialysis subjects with anemia associated with CKD demonstrated that daprodustat could maintain hemoglobin up to 24 weeks with minimal effects on plasma erythropoietin (EPO) concentration. Daprodustat is postulated to be associated with fewer major adverse cardiovascular events by raising hemoglobin without the supraphysiologic EPO concentrations associated with intravenous (IV) rhEPO therapy, potentially avoiding blood pressure (BP) elevations and other adverse effects of high EPO levels. This randomized, open-label (sponsor blind) study will comprise three study periods: a screening period of 2 weeks (can be extended by an additional 4 weeks as needed), a 52-week active treatment period, and a follow-up period of 4 to 6 weeks. Approximately 300 subjects or 150 subjects per treatment group will be randomized 1:1 to receive daprodustat or rhEPO (darbepoetin alfa).
  • Drug: Daprodustat
    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.
    • Drug: Darbepoetin alfa
      Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 40, 60, 100 and 150 mcg.
      • Drug: Iron therapy
        Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.
        Ages eligible for Study
        18 Years to 99 Years
        Genders eligible for Study
        Accepts Healthy Volunteers
        Inclusion Criteria:
        • 18 to 99 years of age inclusive.
        • Planning to start chronic dialysis within the next 4 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: Hemodialysis (HD) >=2 times per week or daily peritoneal dialysis (PD) (Including continuous and automated PD).
        • 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. Note: The country-specific requirements for France will be followed for the informed consent process.
        • The country-specific requirements for France only for the eligibility for inclusion in this study will be followed.
        Exclusion Criteria:
        • Planned living-related donor 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: 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 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, hypoalbuminaemia, 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 an investigational drug (other than daprodustat - see next criterion) <=30 days or within five half-lives of the investigational agent, whichever is longer prior to screening.
        • 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.

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        10 May, 2017
        16 July, 2017
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