Anemia Study in Chronic Kidney Disease (CKD) : Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat -Forearm Blood Flow (ASCEND-FBF)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Daprodustat; Darbepoetin alfa; Acetylcholine; Sodium nitroprusside; L-N-monomethyl arginine acetate (L-NMMA)
Intervention description: Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food.; Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks.; Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.; Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.; L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.
Intervention MeSH terms: Nitroprusside; Acetylcholine; Darbepoetin alfa; omega-N-Methylarginine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized to either daprodustat or darbepoetin alfa. A central randomization approach will be used with stratification by center.
Masking: None (Open Label)
Masking description: This is an open-label study. However, a central FBF reader, who will read and evaluate the FBF data, will be blinded to the treatment assignment.
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: darbepoetin alpha; challenge agents; daprodustat; FBF-CKD

Summary:

      Daprodustat has demonstrated an ability to effectively raise hemoglobin concentrations with
      lower erythropoietin (EPO) levels than those observed after administration of recombinant
      human erythropoietin (rhEPOs). Therefore, daprodustat has the potential to treat anemia of
      chronic kidney disease (CKD) with a lower cardiovascular (CV) risk than is observed with the
      rhEPOs. While the effect of rhEPOs on endothelial function has been assessed, to date the
      effect of daprodustat or other prolyl hydroxylase inhibitor (PHI) compounds on endothelial
      function has not. Therefore, the purpose of this study is to compare the effect of
      daprodustat to darbepoetin alfa on endothelial function by assessing FBF in participants with
      anemia of CKD by using venous occlusion plethysmography as a means to estimate the potential
      for daprodustat to have a lower risk of CV events as compared to rhEPO.

      This study will use a randomized, repeat dose, open label, parallel group design, in adult,
      not on-dialysis, male and female participants with anemia of CKD that are currently not
      treated with rhEPOs.

      The study will comprise of three study periods: a screening period starting up to 30 days
      prior to Day 1, a 42 day (6 week) treatment period, and a follow-up visit up to 14 days
      later. The total duration of participants involvement is up to 14 weeks (including screening
      and follow up visit). Approximately 50 participants will be randomized to either daprodustat
      or darbepoetin alfa.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant must be at least 18 years of age inclusive, at the time of signing the
             informed consent.

          -  Participants who are Stage 3, 4 or 5 CKD defined by estimated Glomerular Filtration
             Rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.

          -  Hemoglobin as measured by HemoCue at screening visit and Day 1 is <=11.0
             grams/deciliter (g/dL) [<=110 gram/Litre (g/L)].

          -  Palpable brachial artery as assessed at screening.

          -  Participants, if necessary may be on stable maintenance oral iron supplementation
             (<50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks
             prior to and including the screening period). If participants have been on intravenous
             (IV) iron, then participants will not have received IV iron for 4 weeks prior to the
             Day 1 visit.

          -  Male or female participants will be included.

          -  A female participant 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 has been on an approved form of
             contraceptive for the 4 weeks prior to Day 1 and agrees to follow the contraceptive
             guidance until the Follow-up visit.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  On dialysis or clinical evidence of impending need to initiate dialysis within 12
             weeks of Day 1.

          -  Planned kidney transplant within 12 weeks of Day 1.

          -  Presence of an arteriovenous (AV) fistula.

          -  Recombinant human erythropoietin use within the 12 weeks prior to the screening visit
             and through Day 1.

          -  History of severe allergic or anaphylactic reactions or hypersensitivity to the study
             treatment or challenge agents, or excipients in the study treatments or challenge
             agents.

          -  Planned use of any prescription or non-prescription drugs or dietary supplements that
             are prohibited from screening until all assessments on Day 42 have been successfully
             completed.

          -  The participant has participated in a clinical trial and has received an experimental
             investigational product within the prior 30 days or within 5 half-lives of the
             investigational product (whichever is longer) prior to screening and through Day 1.

          -  At or below the lower limit of the reference range at screening for Vitamin B12 (may
             rescreen in a minimum of 8 weeks).

          -  Ferritin <=50 nanograms/milliliter [<=50 microgram/liter (µg/L)] at screening.

          -  Transferrin saturation (TSAT) <=15% (0.15) at screening.

          -  Folate <2.0 nanogram/milliliter (4.5 nanomoles/liter; may rescreen in a minimum of 8
             weeks) at screening.

          -  High sensitivity C-reactive protein (hs-CRP) >=50 micrograms/milliliter (>=50 mg/L) at
             screening.

          -  Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening and
             through Day 1.

          -  Hospitalization for greater than 24 hours <=12 weeks prior to screening and through
             Day 1.

          -  Stroke or transient ischemic attack <=12 weeks prior to screening and through Day 1.

          -  Class 4 heart failure, as defined by the New York Heart Association (NYHA) functional
             classification system.

          -  Resting SBP >180 millimeters of mercury (mmHg) or DBP >110 mmHg at screening visit or
             current uncontrolled hypertension as determined by the investigator.

          -  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
             corrected QT (QTc) exclusion for participants with a predominantly ventricular paced
             rhythm.

          -  Active chronic inflammatory disease that could impact erythropoiesis.

          -  History of bone marrow aplasia or pure red cell aplasia.

          -  Conditions, other than anemia of CKD, which can affect erythropoiesis.

          -  Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or
             clinically significant gastrointestinal bleeding from <=8 weeks prior to screening and
             through Day 1.

          -  ALT >2 times upper limit of normal (ULN; screening only).

          -  Bilirubin >1.5 times ULN (screening only); Isolated bilirubin >1.5 times ULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Major surgery within the 12 weeks prior to screening and through Day 1, or planned
             during the study.

          -  Anticipated or planned vascular access surgery (i.e., arteriovenous [AV] fistula)
             within the 12 weeks prior to screening and through the Day 42 assessments.

          -  Received a tissue heart valve replacement or repair within the 6 months prior to
             screening or has received a mechanical heart valve replacement.

          -  Blood transfusion within 6 weeks prior to screening and through Day 1, or an
             anticipated need for blood transfusion during the study.

          -  Clinical evidence of an acute infection, or history of infection requiring IV
             antibiotic therapy from 8 weeks prior to screening and through Day 1. Prophylactic
             oral antibiotics are allowed.

          -  History of malignancy within the two years prior to screening and through Day 1 or
             currently receiving treatment for cancer, with the exception of localized squamous
             cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.

          -  Platelet count <50,000/µL (<50 Giga cells per liter).

          -  History of a bleeding disorder (e.g., hemophilia).

          -  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.