A Study to Evaluate Safety and Efficacy of GSK1278863 in Non-Dialysis Dependent (NDD) Subjects With Anemia Associated With Chronic Kidney Diseases (CKD)
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; rhEPO
Intervention description: Film-coated tablets containing 0.5 mg, 1 mg, 2 mg, 5mg or matching placebo; Locally sourced rhEPO. All subjects who are randomized to the Control arm will receive rhEPO (epoetins or their biosimilars, or darbepoetin) as necessary per standard of care, to maintain Hgb levels within the target range. The decision around whether a subject requires rhEPO, selection of the type of rhEPO and rhEPO dose should be based on Investigator clinical judgment, with the historical rhEPO dose (where applicable) and the current Hgb value being considered..
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 252.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Prolyl hydroxylase inhibitor; pharmacokinetics; GSK1278863; Anemia; hemoglobin; erythropoiesis stimulating agents; Chronic kidney disease

Summary:

      This study will be conducted in approximately 228 subjects with anemia associated with CKD
      who are not on dialysis. Two groups of subjects will be enrolled into the study: Group 1:
      recombinant human erythropoietin (rhEPO) naive subjects; Group 2: rhEPO users, who are
      currently receiving rhEPO. Subjects who are rhEPO naive will be randomized to receive either
      GSK1278863 once daily (QD) or rhEPO in a 3:1 fashion; subjects who are receiving an rhEPO
      before enrolling (rhEPO users) will be randomized in a 1:1 fashion to GSK1278863 QD or to the
      control arm. For those randomized to the control arm, the decision around whether the subject
      requires rhEPO, the selection of the type of rhEPO (if needed) and the choice of rhEPO dose
      to achieve and maintain Hgb concentrations within the target range should be based on
      Investigator clinical judgment, with the historical rhEPO dose and the current Hgb value
      being considered. The study consists of a screening phase of at least 4 weeks, a 24-week
      treatment phase and a follow-up visit that will occur approximately 4 weeks after completing
      treatment. 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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: >=18 years of age. (Week -4 verification only)

          -  Gender: Female and male subjects. (Week -4 verification only) 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
             amenorrhea. 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.

          -  Corrected QT interval (QTc): Bazett's Correction of QT Interval (QTcB) <470
             milliseconds (msec) or QTcB <480 msec in subjects with bundle branch block. There is
             no QTc criterion for subjects with a predominantly paced rhythm.

          -  CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 defined
             by electronic estimated glomerular filtration rate (eGFR) using the CKD Epidemiology
             Collaboration (CKD-EPI) formula.

          -  Hgb: Group 1 (rhEPO naïve): Baseline Hgb of 8.0-11.0 g/dL (inclusive) (USA sites only:
             8.0-10.0 g/dL, inclusive); Group 2 (rhEPO users): Baseline Hgb of 9.0-11.5 g/dL
             (inclusive) (USA sites only: 9.0-10.5, inclusive).

          -  Stable rhEPO dose for rhEPO users: Group 2 subjects must be using the same rhEPO
             (epoetins or their biosimilars, or darbepoetin) with total weekly doses that varied by
             no more than 50% during the 4 weeks prior to Week -4. At Day 1 (randomization),
             confirm that total weekly doses varied by no more than 50% during the screening
             period.

          -  Oral iron therapy: If on oral iron, then doses must not be changed for the 4 weeks
             prior to Week -4, during the screening phase, and through the first 4 weeks after
             Randomization.

        Exclusion Criteria:

          -  Dialysis: On dialysis or planning to initiate dialysis during the study.

          -  Renal transplant: Pre-emptive or scheduled renal transplant.

          -  High rhEPO dose: An epoetin dose of >=360 IU/kg/week intravenous (IV) or >=250
             IU/kg/week subcutaneous (SC) or darbepoetin dose of >=1.8 microgram per kilogram per
             week (mcg/kg/week) IV or SC within the prior 8 weeks through Day 1 (randomization).

          -  Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Day 1
             (randomization).

          -  IV iron therapy: Use of IV iron for 4 weeks prior to Screening Week -4, during the
             screening phase, and through the first 4 weeks after Randomization

          -  Vitamin B12: Below the lower limit of the reference range (may rescreen in a minimum
             of 8 weeks).

          -  Folate: <2.0 nanogram per millilitre (ng/mL) (<4.5 nanomoles per liter [nmol/L]) (may
             rescreen in a minimum of 4 weeks).

          -  Ferritin: <40 ng/mL (<40 mcg/L).

          -  Transferrin saturation (TSAT): Below the lower limit of the reference range

          -  Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to
             Screening through Day 1 (randomization).

          -  Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4 Screening
             through Day 1 (randomization).

          -  Heart failure: Class III/IV heart failure as defined by the New York Heart Association
             (NYHA) functional classification system diagnosed prior to Week -4 Screening through
             Day 1 (randomization), symptomatic right heart failure diagnosed prior to Week -4
             Screening through Day 1 (randomization).

          -  Uncontrolled hypertension: Defined as diastolic blood pressure (DBP) >100 mmHg or
             systolic blood pressure (SBP) >170 mmHg at Week -4 and reconfirmed at Day 1.

          -  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 Week -4 Screening through Day 1 (randomization).

          -  Ophthalmology disease: Meeting any ophthalmologic-related exclusion criteria
             determined at the Screening ophthalmology exam.

          -  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 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 other than renal disease diagnosed prior to Week -4 Screening through
             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) >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.

          -  Major surgery: Major surgery (excluding vascular access surgery) within the prior 8
             weeks, during the Week -4 Screening phase or planned during the study.

          -  Transfusion: Blood transfusion within the prior 8 weeks, during the Week -4 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 Week -4 Screening through Day 1 (randomization).

          -  Acute infection: Clinical evidence of acute infection or history of infection
             requiring IV antibiotic therapy within the 8 weeks prior to Week -4 Screening through
             Day 1 (randomization).

          -  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 Week -4 Screening
             through Day 1 (randomization).

          -  Severe allergic reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product (see GSK1278863 IB for
             list of excipients and rhEPO (refer to local product labelling for details).

          -  Drugs and supplements: Use of any prescription or non-prescription drugs or dietary
             supplements that are prohibited from Week -4 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 Week -4 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.

          -  Patient participation: Unwillingness or inability of the subject to follow the
             procedures or lifestyle or dietary restrictions outlined in the protocol.

          -  Pregnancy or Lactation: Pregnant females as determined by positive urine human
             chorionic gonadotropin (hCG) test OR women who are lactating at Week -4 Screening or
             during the trial.