Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; Placebo
Intervention description: GSK1278863 will be supplied as film coated tablets for oral administration containing 1 mg, 2 mg, or 5 mg of GSK1278863.; Film coated tablets of GSK1278863 matching placebo for oral administration.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 97.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Hemodialysis; GSK1278863; Pharmacokinetics; Erythropoiesis Stimulating Agents; Chronic Kidney Disease; Hemoglobin; Recombinant Erythropoietin; Prolyl Hydroxylase Inhibitor; Anemia

Summary:

      This study aims to characterize the relationship between dose of GSK1278863 and hemoglobin
      (Hgb) response in hemodialysis-dependent (HDD) subjects with anemia associated with chronic
      kidney disease (CKD). It is anticipated that the data generated will enable selection of the
      starting dose(s) and optimize dose adjustment regimen(s) for Phase 3 clinical trials. This
      study will consist of a screening phase of 3-9 weeks, a 4-week treatment phase and a
      follow-up visit approximately 4 weeks after completing treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age (Informed concent): Japanese >=20 years of age

          -  Gender (Screening 2 verification only): Female and male

          -  Females: must be of childbearing potential, and must agree to use one of the approved
             contraception methods from Screening 2 until completion of the Follow-up Visit. OR Of
             non-childbearing potential defined as pre-menopausal females with a documented tubal
             ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous
             amenorrea [in questionable cases a blood sample with simultaneous follicle stimulating
             hormone 23.0 - 116.3 million international units (MIU)/millilitre (mL) and estradiol
             <= 10 picograms (pg)/mL is confirmatory]. Females on hormone replacement therapy (HRT)
             whose menopausal status is in doubt will be required to use one of the approved
             contraception methods if they wish to continue their HRT during the study. Otherwise
             they must discontinue HRT to allow confirmation of post-menopausal status prior to
             study enrolment. For most forms of HRT, at least 2 weeks will elapse between the
             cessation of therapy and the blood draw; this interval depends on the type and dosage
             of HRT. Following confirmation of their post-menopausal status, they can resume use of
             HRT during the study without use of a contraceptive method. Males: must agree to use
             one of the approved contraceptive methods from the time of Screening 2 until
             completion of the Follow-up Visit.

          -  Corrected QT interval (QTc) (Screening 2 verification only): Bazett's Correction of QT
             Interval (QTcB) <470 milliseconds (msec) or QTcB <480 msec in subjects with bundle
             branch block. There is no QTc inclusion criterion for a subject with a predominantly
             paced rhythm.

          -  Dialysis frequency: On hemodialysis (HD) three times weekly for at least 8 weeks prior
             to Screening 2 through Day 1.

          -  Dialysis adequacy (Screening 2 only): A single-pool Kt/Vurea of 1.2 based on a
             historical value obtained within the prior month 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%.

          -  Hemoglobin: Target stable Hgb between 9.5-12.0 g/dL at screening.

          -  Stable erythropoiesis-stimulating agent (ESA) dose (Screening 2 only): Using the same
             ESA (epoetins or their biosimilar, or darbepoietin) with total weekly doses that
             varied by no more than 50% during the 4 weeks prior to Screening 2.

          -  Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous
             (IV) (<100 milligrams [mg]/week) iron supplementation. If subjects are on oral or IV
             iron, then doses must be stable for the 4 weeks prior to Screening 2, and Screening 2
             through Week 4.

        Exclusion Criteria:

          -  Dialysis modality: Planned change from HD to peritoneal dialysis within the study time
             period.

          -  Renal transplant: Renal transplant anticipated or scheduled within the study time
             period.

          -  High ESA dose (Screening 2 verification only): As defined by an epoetin dose of >=360
             IU/kilograms (kg)/week IV or darbepoetin dose of >=1.8 micrograms (μg)/kg/week IV
             within the prior 8 weeks through Screening 2.

          -  methoxy polyethylene glycol epoetin beta (Screening 2 verification only): Use of
             methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Screening 2.

          -  Vitamin B12: At or below the lower limit of the reference range

          -  Folate: <2.0 nanograms (ng)/mL (<4.5 nanomoles [nmol]/liters [L])

          -  Iron status: Ferritine <100 ng/mL (<100 μg/L) AND Transferrin saturation (TSAT) <20%

          -  Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to
             Screening 2 through Day 1.

          -  Stroke or transient ischemic attack: Within the 8 weeks prior to Screening 2 through
             Day 1.

          -  Heart failure: Class III/IV heart failure, as defined by the New York Heart
             Association (NYHA) functional classification system or symptomatic right heart failure
             diagnosed prior to Screening 2 through Day 1.

          -  Hypertension: Defined using pre-dialysis vitals of diastolic blood pressure >100 mmHg
             or systolic blood pressure >170 mmHg.

          -  Thrombotic disease: History of thrombotic disease (e.g., venous thrombosis such as
             deep vein thrombosis or pulmonary embolism, or arterial thrombosis such as new onset
             or worsening limb ischemia requiring intervention), except vascular access thrombosis,
             within the 8 weeks prior to Screening 2 through Day 1

          -  Eyes: History of proliferative retinopathy requiring treatment within the prior 12
             months or macular edema requiring treatment..

          -  Inflammatory disease: Active chronic inflammatory disease that could impact
             erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis,
             celiac disease) diagnosed prior to Screening 2 through Day 1.

          -  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 other than renal disease diagnosed prior to Screening 2 through Day 1.

          -  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) >2.0 x upper limit of normal (ULN) or total bilirubin > 1.5 x ULN]; or other
             hepatic abnormalities that in the opinion of the investigator (subinvestigator) would
             preclude the subject from participation in the study.

          -  Major surgery: Major surgery (excluding vascular access surgery) within the prior 8
             weeks, within the Screening 2 to Day 1 or planned during the study.

          -  Transfusion: Blood transfusion within the prior 8 weeks, within the Screening 2 to Day
             1 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 2 through Day 1.

          -  Acute infection: Clinical evidence of acute infection or history of infection
             requiring IV antibiotic therapy within 8 weeks prior to Screening 2 through Day 1.

          -  Malignancy: Subjects with a history of malignancy within the prior 5 years, who
             receiving treatment for cancer, or who have a strong family history of cancer (e.g.,
             familial cancer disorders); with the exception of squamous cell or basal cell
             carcinoma of the skin that has been definitively treated prior to Screening 2 through
             Day 1.

          -  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 from Screening 2 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 2 through Day 1.

          -  Pregnancy or lactation: Pregnant females as determined by positive serum Human
             Chorionic Gonadotrophin (hCG) test (Screening 2 only) OR women who are lactating at
             Screening 2 and/or Day 1 or during the trial.

          -  Other conditions: Any other condition, clinical or laboratory abnormality, or
             examination finding that the Investigator would consider inappropriate to participate
             in the study.