Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of GSK1278863 in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; GSK1278863 matching Placebo
Intervention description: GSK1278863 will be supplied as a round, biconvex, 10 millimeter (mm) white film coated tablet with the unit dose strength of 5 mg and 25 mg.; GSK1278863 matching placebo will be supplied as a round, biconvex, 10 mm white film coated tablet.
Intervention MeSH terms: Glycine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 103.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Chronic kidney disease; Efficacy; Erythropoiesis-stimulating agent; GSK1278863; Safety; Hemodialysis-dependent anemia; Pharmacokinetics

Summary:

      GSK1278863 is an orally available, hypoxia-inducible factor - prolyl hydroxylase inhibitor,
      currently being investigated as a treatment for anemia associated with chronic kidney
      disease. GSK1278863 has been given as a once daily regimen in clinical studies to date.
      However, physicians in countries that use a three-times weekly hemodialysis schedule prefer
      to give the anemia medicine at the same time as the dialysis session. This study will test
      how well GSK1278863 can maintain hemoglobin levels when given three-times weekly, for 29
      days.

      This study will describe the relationship between hemoglobin and GSK1278863 given three-times
      weekly. The data from this study will allow for conversion of once daily doses to three-times
      weekly doses.
    

Eligibility criteria:

        Inclusion Criteria:

          -  More than or equal to 18 years of age, at the time of signing the informed consent.

          -  Hemoglobin: Stable Hemoglobin 9.0 - 11.5 gram per deciliter (g/dL).

          -  Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three to
             five times weekly for at least 4 weeks prior to Day -28 Screening through Day 29.

          -  Dialysis adequacy: A single pool Kt/Vurea of >=1.2 based on a historical value
             obtained within the prior three months 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 (URR) of at least 65 percent. NOTE: Only needs confirming at Day -28.

          -  Erythropoiesis-stimulating agent (ESA)dose: Treated with the same ESA (epoetins or
             their biosimilars, or darbepoetin or methoxy polyethylene glycol [PEG]-epoetin beta)
             with total weekly dose varying by no more than 50 percent during the 4 weeks prior to
             Day -28.

          -  Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous
             (IV) (<=100 milligram (mg)/week) iron supplementation. If subjects are on oral or IV
             iron, then doses must be stable for the 4 weeks prior to Day -28, during the screening
             phase, and through the 29 days of treatment.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in study protocol.

        Exclusion Criteria:

          -  Dialysis modality: Planned change from HD to peritoneal dialysis within the study time
             period.

          -  Renal transplant: Planned for living-related kidney transplant.

          -  High ESA dose: An epoetin dose of >=360 international unit (IU)/kilogram (kg)/week IV
             or >=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of >=1.8 microgram
             (mcg)/kg/week IV or SC or methoxy PEG-epoetin beta dose of >= 2.2 mcg/kg/week within
             the prior 8 weeks through Day 1 (randomization).

          -  Administration of methoxy PEG-epoetin beta within the prior 4 weeks through Day 1
             (randomization).

          -  Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to
             Screening through Day 1 (randomization).

          -  Stroke or transient ischemic attack: Within 8 weeks prior to Screening though Day 1
             (randomization).

          -  Heart failure: Class IV heart failure, as defined by the New York Heart Association
             (NYHA) functional classification system diagnosed prior to Screening through Day 1
             (randomization).

          -  Correction of Q-T Interval using Bazett's formula (QTcB): QTcB >500 millisecond (msec)
             or QTcB >530 msec in subjects with Bundle Branch Block. There is no correction of Q-T
             Interval (QTc) exclusion for subjects with a predominantly paced rhythm.

          -  Inflammatory disease: Active chronic inflammatory disease that could impact
             erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis,
             celiac disease) diagnosed prior to Screening through Day 1 (randomization).

          -  Hematological disease: Any hematological disease including those affecting platelets,
             white or red blood cells (e.g., sickle cell anemia, myelodysplastic syndromes,
             hematological malignancy, myeloma, hemolytic anemia and thalassemia), coagulation
             disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or any other
             cause of anemia of chronic disease other than renal disease diagnosed prior to
             Screening though Day 1 (randomization).

          -  Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the
             exception of Gilbert's syndrome or asymptomatic gallstones) or evidence at Screening
             of abnormal liver function tests [alanine transaminase (ALT) or aspartate transaminase
             (AST) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN]; or other hepatic
             abnormalities that in the opinion of the investigator would preclude the subject from
             participating in the study.

        NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions are not
        met.

          -  Major surgery: Major surgery (excluding vascular access surgery) within the 8 weeks
             prior to Screening, during the Screening phase, or planned during the study.

          -  Transfusion: Blood transfusion within the 8 weeks prior to Screening, during the
             Screening phase or an anticipated need for blood transfusion during the study.

          -  Gastrointestinal (GI) Bleeding: Evidence of actively bleeding peptic, duodenal, or
             esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks
             prior to Screening through Day 1 (randomization).

          -  Acute Infection: Clinical evidence of acute infection or history of infection
             requiring IV antibiotic therapy within the 4 weeks prior to Screening through Day 1
             (randomization). NOTE: IV antibiotics as prophylaxis are allowed.

          -  Malignancy: History of malignancy within the two years prior to randomization or
             currently receiving treatment for cancer, or has a known >=4 centimeter complex kidney
             cyst (i.e. Bosniak Category II F, III of IV). NOTE: ONLY exception is squamous cell or
             basal cell carcinoma of the skin that has been definitively treated >=8 weeks prior to
             Screening.

          -  Severe allergic reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product

          -  Drugs and supplements: Use of any prescription or non-prescription drugs or dietary
             supplements that are prohibited (as per protocol) from Screening until the Follow-up
             Visit.

          -  Prior investigational product exposure: The Subject has participated in a clinical
             trial and has received an experimental investigational product within the prior 30
             days from Screening through Day 1 (randomization).

          -  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 or prevent understanding of the
             aims or investigational procedures or possible consequences of the study.

          -  Females ONLY: A female subject is not eligible to participate if she is pregnant [as
             confirmed by a positive serum human chorionic gonadotrophin (hCG) test for females of
             reproductive potential (FRP) only], breastfeeding, and if of reproductive potential
             does not agree to follow one of the options listed in the GSK Modified List of Highly
             Effective Methods for Avoiding Pregnancy in FRP.

          -  Vitamin B12: At or below the lower limit of the reference range (may rescreen in a
             minimum of 8 weeks).

          -  Folate: <2.0 nanogram (ng) per millilitre (mL) (4.5 nanomole/liter [L]) (may rescreen
             in a minimum of 4 weeks).

          -  Ferritin: <100 ng/mL (<100 mcg/L).

          -  Transferrin saturation (TSAT): <20 percent.