4 Week Switch Study in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; rhEPO
Intervention description: tablet; injection
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Renal Impairment; Anemia; pharmacokinetics; hemodialysis; Chronic kidney disease; GSK1278863; hemoglobin; Prolyl hydroxylase inhibitor; recombinant human erythropoietin; erythropoiesis stimulating agents; Dialysis, Renal

Summary:

      This is a four-week, Phase IIa, randomized, active-controlled, parallel-group, multi-center
      study to evaluate the safety, efficacy and pharmacokinetics of switching subjects from stable
      rhEPO to GSK1278863 in approximately 68 hemodialysis-dependent subjects with anemia
      associated with chronic kidney disease. The study consists of a screening phase of 2 weeks, a
      4-week treatment phase and a 2-week follow-up phase. The range of Hgb values for study
      eligibility is 9.5-12.0 g/dL and the subjects must have received the same rhEPO product with
      total weekly doses that varied by no more than 50% during the 4 weeks prior to the Screening
      visit (Week -1. This study aims to estimate the relationship between dose of GSK1278863 and
      Hgb response in hemodialysis-dependent (HDD) subjects with anemia associated with chronic
      kidney disease after switching from a stable maintenance dose of recombinant human
      erythropoetin (rhEPO).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age and weight: >/=18 years of age and >/=45 kg (weight post-dialysis).

          2. On three times weekly hemodialysis for at least 8 weeks, irrespective of eGFR values
             and stage of chronic kidney disease (CKD).

          3. 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%.

          4. rhEPO use: Using the same rhEPO (epoetins or darbepoetin) with total weekly doses that
             varied by no more than 50% during the prior 4 weeks (i.e., maximum vs. minimum total
             weekly doses </=50%).

          5. Hgb concentrations 9.5-12.0 g/dL (inclusive).

          6. Vitamin B12 above the lower limit of the reference range (may rescreen in two months).

          7. Folate: >/= 2.0 ng/mL (may rescreen in one month).

          8. Ferritin: >/=40 ng/mL with the absence of microcytic or hypochromic RBCs.

          9. Transferrin saturation (TSAT): Within the reference range.

         10. Iron replacement therapy: Stable maintenance dose of oral iron replacement therapy, if
             required, that will be maintained throughout the study. NOTE: IV iron replacement
             therapy is not allowed the two weeks prior to Screening through the end of the study
             (Week 6).

         11. QTc: QTcB <470 msec or QTcB <480 msec in subjects with bundle branch block obtained at
             Screening Visit (based on Central Reader's interpretation).

         12. Females: Eligible to participate if she is of childbearing potential, and 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 of hysterectomy; or postmenopausal defined as 12
             months of spontaneous amenorrhea [in questionable cases a blood sample with
             simultaneous follicle stimulating hormone (FSH)>40MIU/ml and estradiol <40pg/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.

         13. Males: Must agree to use one of the approved contraceptive methods from the time of
             Screening until completion of the Follow-up Visit.

        Exclusion Criteria:

          1. Dialysis modality: On peritoneal dialysis OR planned change in dialysis modality
             within the study time period.

          2. rhEPO Hyporesponders: As defined by an epoetin dose of >/=360 IU/kg/week IV or
             darbepoetin dose of >/=1.8 µg/kg/week IV within the prior 8 weeks.

          3. Renal transplant: Renal transplant anticipated or scheduled within the study time
             period or subjects with a functioning renal transplant.

          4. Mircera or Peginesatide: Current or prior use (within the prior 8 weeks) of Mircera
             (methoxy polyethylene glycol epoetin beta) OR peginesatide.

          5. Total CPK: >5x the upper limit of the reference range.

          6. HIV: Positive HIV antibody.

          7. History of myocardial infarction or acute coronary syndrome within the prior 6 months.

          8. History of stroke or transient ischemic attacks (TIAs) within the prior 6 months.

          9. Heart failure: Class III/IV heart failure, as defined by the New York Heart
             Association (NYHA) functional classification system.

         10. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or
             lack of treatment, is defined as follows:

               -  DBP >100 mmHg or SBP>160 mmHg for subjects taking hypertension medication(s)
                  before screening and dialysis, if required.

               -  DBP >105 mmHg or SBP>170 mmHg for subjects who are asked to hold hypertension
                  medication(s) before screening and dialysis.

         11. 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), or other thrombosis related
             condition except shunt thrombosis) within the prior 6 months.

         12. Pulmonary hypertension: Known pulmonary hypertension and those at higher risk (than
             normally associated with CKD) for pre-existing elevation in pulmonary pressure (e.g.,
             significant heart failure or lung disease requiring supplemental oxygen, or those with
             connective tissue diseases).

         13. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis
             (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac
             disease).

         14. Haematological disease: Any haematological disease including those affecting
             platelets, the coagulation disorders (e.g., Protein C or S deficiency) or red blood
             cells (e.g. sickle cell anemia, myelodysplastic syndromes, haematological malignancy,
             myeloma, haemolytic anemia) or any other cause of anemia other than renal disease.

         15. 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 [alkaline phosphatase, 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.

         16. Major surgery: (excluding vascular access surgery) Within the prior 12 weeks or
             planned during the study.

         17. Transfusion: Blood transfusion within the prior 12 weeks or an anticipated need for
             blood transfusion during the study.

         18. Ulcer and Active GI Bleeding: Evidence of active peptic, duodenal, or esophageal ulcer
             disease OR GI bleeding within the prior 12 weeks.

         19. Acute infection: Clinical evidence of acute infection or history of infection
             requiring intravenous (IV) antibiotic therapy the eight weeks prior to Screening
             through Day 1 (randomization).

         20. Malignancy: History of malignancy within the prior 5 years or are receiving treatment
             for cancer or those with 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.

         21. Eyes: History of proliferative retinopathy requiring treatment within the prior 12
             months or macular edema requiring treatment.

         22. Severe reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product.

         23. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary
             supplements that are prohibited from Screening until the Follow-up Visit.

         24. Androgens: New androgen therapy or changes to pre-existing androgen regimen within the
             prior 12 weeks.

         25. Prior investigational product exposure: The Subject has participated in a clinical
             trial and has received an experimental investigational product within the prior 30
             days.

         26. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle
             and/or dietary restrictions outlined in the protocol.

         27. Other Conditions: Any condition which in the investigator's opinion should exclude the
             subject from participating in the study.

         28. Pregnancy or Lactation: Pregnant females as determined by positive serum hCG test OR
             women who are lactating at Screening or during the trial.