Anemia Study in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat; Epoetin alfa
Intervention description: Daprodustat will be available as oral tablets at unit dose strength of 1, 2, 4, 6, 8 and 10 mg.; Epoetin alfa will be administered according to local labelling and clinical practice guidelines to keep Hgb in the target range (10.0-11.0 g/dL)
Intervention MeSH terms: Epoetin Alfa
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 105.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Anemia; Daprodustat; Blood pressure; ESA; CKD

Summary:

      This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD)
      participants with anemia associated with chronic kidney disease (CKD), designed to compare
      the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be
      screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA)
      washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1
      and stratified by prior ESA dose before they undergo Acute Challenge 1, a single dose
      challenge to compare the acute effects on BP of the highest planned once-daily maintenance
      dose of daprodustat (24 milligrams [mg]) to the highest starting dose of epoetin alfa (100
      units/kilogram [U/kg]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance
      period, where doses of either daprodustat or epoetin alfa will be administered and adjusted.
      At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated
      utilizing the same treatment dose administered in Acute Challenge 1; there will be a
      follow-up visit within 14+/-3 days after completing treatment.
    

Eligibility criteria:

        Inclusion Criteria

          -  More than or equal to 40 years of age, at the time of signing the informed consent

          -  Stable Hgb 8.5 to 11.5 grams per deciliter (g/dL) inclusive.

          -  Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three-to
             five-times weekly for at least 4 weeks prior to screening.

          -  A single pool Kt/Vurea >=1.2 based on a historical value obtained within 3 months
             prior to screening in order to ensure the adequacy of dialysis. If Kt/Vurea is not
             available, then an average of the last 2 values of urea reduction ratio should be at
             least 65 percent (%).

          -  Treated with an ESA (epoetins or their biosimilars, darbepoetin, or methoxy
             polyethylene glycol [PEG]-epoetin beta) for at least 4 weeks prior to screening.

          -  Participants may be on stable (<=50% change in overall dose and compliance of 80% of
             prescribed doses in the 4 weeks prior to and including the screening period)
             maintenance oral or intravenous (IV; <=100 mg/week) iron supplementation. If
             participants are on oral or IV iron, then doses must be stable for the 4 weeks prior
             to Washout.

          -  Weight: Mid-week weight change between dialysis treatments <5% as assessed
             post-dialysis at the Screening and Washout visits.

          -  On at least 1 antihypertensive medication (excluding diuretics) and on that same
             medication and the same dose for at least 1 week prior to Washout.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and the protocol.

          -  Willing and able to wear ABPM device for at least 25 hours on two separate sessions.

        Exclusion Criteria

          -  Planned change from HD to peritoneal dialysis within the study time period, or on home
             dialysis.

          -  Planned for kidney transplant within the 16 weeks following the Screening visit.

          -  An epoetin alfa dose of >=360 U/kg/week IV or >=250 U/kg/week subcutaneous (SC), or
             darbepoetin dose of >=1.8 micrograms (μg)/kg/week IV or SC, or methoxy PEG-epoetin
             beta dose of >=2.2 μg/kg/week within the 8 weeks prior to screening through Week -4.

          -  Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) within the 4
             weeks prior to the Washout.

          -  Occurrence of myocardial infarction or acute coronary syndrome within 3 months prior
             to Washout.

          -  Stroke or transient ischemic attack within 3 months prior to Washout.

          -  Chronic Class 4 heart failure, as defined by the New York Heart Association functional
             classification system diagnosed prior to Washout.

          -  QT interval corrected for heart rate using Bazett's formula (QTcB) >500 milliseconds
             (msec), or QTcB >530 msec in participants with Bundle Branch Block. There is no QTc
             exclusion for participants with a predominantly paced rhythm.

          -  Resting post dialysis SBP >160 millimeters of mercury (mmHg); or DBP >100 mmHg at
             screening or uncontrolled hypertension as determined by the investigator.

          -  Presence of atrial fibrillation.

          -  Active chronic inflammatory disease that could impact erythropoiesis (e.g.,
             scleroderma, systemic lupus erythematosus, rheumatoid arthritis, celiac disease)
             diagnosed prior to Washout.

          -  History of bone marrow aplasia or pure red cell aplasia.

          -  Other causes of anemia including Pernicious anemia, thalassemia major, sickle cell
             disease or myelodysplastic syndrome.

          -  Alanine transaminase (ALT) >2 times upper limit of normal (ULN) (screening only) or
             Bilirubin >1.5 times ULN (screening only) 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.

          -  Major surgery (excluding vascular access surgery) within the 3 months prior to Washout
             or planned during the study.

          -  Blood transfusion within the 8 weeks prior to Washout or an anticipated need for blood
             transfusion during the study.

          -  Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or
             clinically significant gastrointestinal bleeding within the 8 weeks prior to Washout.

          -  Clinical evidence of acute infection or history of infection requiring IV antibiotic
             therapy within the 8 weeks prior to Washout.

          -  History of malignancy within the two years prior to screening through Day 1 or
             currently receiving treatment for cancer, or has a known complex kidney cyst (e.g.,
             Bosniak Category IIF, III or IV) >=3 centimeters.

          -  Participants with an upper arm diameter which cannot be measured by oscillometer/
             sphygmomanometer cuff or for whom BP cannot be measured in the opposite arm of current
             vascular access.

          -  History of severe allergic or anaphylactic reactions or hypersensitivity to excipients
             in the investigational product.

          -  Use of any prescription or non-prescription drugs or dietary supplements that are
             prohibited from screening until Washout.

          -  The participant has participated in a clinical trial and has received an experimental
             investigational product within the 30 days prior to Day 1 or within 5 half lives of
             the investigational product prior to screening, whichever is longer.

          -  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.

          -  A female participant is pregnant (as confirmed by a positive serum human chorionic
             gonadotrophin test for females of reproductive potential only), participant is
             breastfeeding, or participant is of reproductive potential and does not agree to
             follow one of the pre-specified contraceptive options

          -  Vitamin B12 at or below the lower limit of the reference range (may rescreen in a
             minimum of 8 weeks, following treatment).

          -  Folate at <2.0 nanograms/milliliter (ng/mL) (4.5 Nanomoles per Liter) (may rescreen in
             a minimum of 4 weeks, following treatment).

          -  Ferritin at <100 ng/mL

          -  Transferrin saturation at <20%.