Study to Evaluate the Safety and Efficacy of GSK1278863 in Recombinant Human Erythropoietin (rhEPO) Hyporesponsive Hemodialysis-dependent Chronic Kidney Disease Subjects With Anemia
Condition: Anemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; Placebo
Intervention description: Film coated tablets containing 1 mg, 2 mg, 5 mg or 25 mg of GSK1278863; Matching placebo tablet for GSK1278863
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recombinant human erythropoietin; GSK1278863; hemodialysis; anemia; Hemoglobin; chronic rhEPO hyporesponsiveness; chronic kidney disease; erythropoiesis stimulating agents; pharmacokinetics

Summary:

      The study will evaluate the ability of GSK1278863 to increase the hemoglobin (Hgb)
      concentration, or maintain it within the target range, and the safety and efficacy of
      GSK1278863 over 16 weeks of treatment, in hemodialysis-dependent subjects with anemia
      associated with chronic kidney disease who are chronically hyporesponsive to rhEPO. The data
      generated will inform dose requirements for any chronic rhEPO hyporesponsive
      hemodialysis-dependent subjects included in future clinical trials. The study consists of a
      4-week rhEPO run-in period, a 16-week GSK1278863 treatment period and a 4-week Follow-up
      period.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Hemodialysis (HD) frequency: Stable HD regimen of three to four times weekly for a
             minimum of 12 weeks. Note: The type and frequency of dialysis must be stable during
             the study. Isolated ultrafiltration sessions for the purposes of fluid removal are
             permitted.

          -  Dialysis Adequacy: Single-pool dialyzer clearance multiplied by dialyzer time divided
             by volume of distribution of urea (Kt/Vurea) of >=1.2 based on a historical value
             obtained within the prior month.

          -  rhEPO hyporesponsiveness: Historical and current intravenous (IV) rhEPO and Hgb
             values. Average epoetin alfa dose and Hgb level for three 4-week periods for a total
             of 12 weeks prior to Week -4, and during the 4 week run-in period, must be within the
             following ranges: average epoetin alfa dose >4000 and <=6000 units per session and Hgb
             >=8.0 and <=9.5 g/dL; average epoetin alfa dose >6000 and <=8000 units per session and
             Hgb >=8.0 and <=10.0 g/dL; average epoetin alfa dose >8000 and <=10000 units per
             session and Hgb >=8.0 and <=10.5 g/dL; and average epoetin alfa dose >10000 units per
             session and Hgb >=8.0 and <=11.0 g/dL.

          -  Absolute difference between the Hgb value at Week -4 and Week 0 (Day 1), must be <1.3
             g/dL. Note: Subjects who do not meet the criteria after being rescreened twice, should
             not be entered into the GSK1278863 treatment period and should be withdrawn from the
             study.

          -  Age: >=18 years of age.

          -  Q-T Interval Corrected for Heart Rate (QTc): Bazett's Correction of QT Interval (QTcB)
             <470 msec or QTcB <480 milliseconds (msec) in subjects with bundle branch block. There
             is no corrected QT interval (QTc) inclusion criterion for a subject with a
             predominantly paced rhythm.

          -  Gender: Female and male subjects. Females: If of childbearing potential, must agree to
             use one of the approved contraception methods from Screening until completion of the
             Follow-up Visit OR, of non-childbearing potential defined as pre-menopausal females
             with a documented tubal ligation, hysterectomy or oophorectomy; or postmenopausal
             defined as 12 months of spontaneous amenorrea [in questionable cases a blood sample
             with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 milliinternational
             units (MIU)/milliliter (mL) (23.0-116.3 international units (IU)/liter (L)) and
             estradiol <=10 picograms (pg)/mL (<=37 picomole (pmol)/L) 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 enrollment. 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.

        Exclusion Criteria:

          -  Dialysis modality: Planned change in dialysis modality within the study time period.

          -  rhEPO: Use of methoxy polyethylene glycol epoetin beta or darbepoetin within the prior
             8 weeks prior to Week -4.

          -  Renal transplant: Scheduled renal transplant.

          -  Transferrin saturation (TSAT): <20% on the most recent sample taken over the last 12
             weeks.

          -  Ferritin: <100 nanograms (ng)/mL (<100 micrograms/L) on the most recent sample taken
             over the last 12 weeks.

          -  Vitamin B12: At or below the lower limit of the reference range (may rescreen in a
             minimum of 8 weeks).

          -  Folate: <2.0 ng/mL (<4.5 nanomoles (nmol)/L) (may rescreen in a minimum of 4 weeks).

          -  Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Week -4.

          -  Stroke or transient ischemic attacks (TIAs): Within the 8 weeks prior to Week -4.

          -  Heart failure: Class III/IV heart failure, as defined by the New York Heart
             Association (NYHA) functional classification system diagnosed prior to Week -4.

          -  Hypertension: Defined using pre-dialysis vitals (Week -4) of diastolic blood pressure
             >100 millimeters of mercury (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) within the 8 weeks prior to Week
             -4, except vascular access thrombosis.

          -  Inflammatory disease: Active chronic inflammatory disease that could impact
             erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis,
             celiac disease) diagnosed prior to Week -4.

          -  Hematological disease: Any hematological disease including those affecting platelets,
             white or red blood cells (e.g., antibody-mediated pure red cell aplasia, sickle cell
             anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic
             anemia), coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S
             deficiency), or any other cause of anemia other than renal disease diagnosed prior to
             Week -4.

          -  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 would preclude the
             subject from participation in the study. NOTE: Those with Hepatitis B or Hepatitis C
             are eligible provided these exclusions are not met.

          -  Major surgery: (excluding vascular access surgery) within the 8 weeks prior to Week
             -4, or planned during the study.

          -  Transfusion: Blood transfusion within the 8 weeks prior to Week -4, 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 Week -4.

          -  Ophthalmology disease: History of proliferative retinopathy requiring treatment within
             the prior 12 months or macular edema requiring treatment.

          -  Acute infection: Clinical evidence of acute infection, evidence of underlying
             infection or history of infection requiring IV antibiotic therapy within the 8 weeks
             prior to Week -4, and also through to Day 1. Note: IV antibiotics as prophylaxis are
             allowed.

          -  Malignancy: Subjects with a history of malignancy within the prior 5 years, who are
             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 Week -4.

          -  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 Week -4 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 to Week -4.

          -  Life Expectancy: Life expectancy is considered by the investigator to be less than 6
             months.

          -  Other conditions: Any other conditions, clinical or laboratory abnormality, or
             examination finding that the Investigator considers would put the subject at
             unacceptable risk, or an unwillingness or inability to follow the procedures, or
             lifestyle and/or dietary restrictions outlined in the protocol.

          -  Pregnancy and lactation: Pregnant females as determined by positive serum human
             chorionic gonadotrophin (hCG) test or women who are lactating at Week -4 or during the
             trial.

          -  Laboratory eligibility criteria will be assessed according to the central laboratory
             result for the screening samples

          -  Subjects who fail screening may be rescreened as soon as the investigator feels they
             may have subsequently become eligible. However, an individual subject may not be
             rescreened more than twice. There is no predetermined amount of time required to wait
             to rescreen a previously ineligible subject. Exceptions are those failing on Hgb or
             folate who may rescreen in 4 weeks and those failing for Vitamin B12 where rescreening
             may occur in 8 weeks.