4 Week Correction Study in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Undergoing Dialysis
Condition: Anaemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: GSK1278863; Placebo
Intervention description: Tablet; Tablet
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Anemia; Prolyl hydroxylase inhibitor; Hemoglobin; Chronic kidney disease; pharmacokinetics; recombinant human erythropoietin; GSK1278863

Summary:

      This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group,
      multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in
      approximately 68 subjects with anemia associated with chronic kidney disease who are not
      taking rhEPO and are not undergoing dialysis. The range of Hgb values for study eligibility
      is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once
      daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age and weight: >/= 18 years of age and >/= 45 kg.

          2. Not routinely undergoing dialysis, regardless of the modality (either hemodialysis or
             peritoneal dialysis) or dialysis planned during the time the subject would be enrolled
             in the study.

          3. No current or prior rhEPO use within the past 7 weeks; e.g., epoetins (or their
             biosimilars), darbepoetin, Mircera (methoxy polyethylene glycol epoetin beta),
             peginesatide or their biosimilars..

          4. KDOQI CKD stages 3/4/5 defined by eGFR using the Modification of Diet for Renal
             Disease (MDRD).

          5. Hgb: Hgb concentrations 8.5-11.0 g/dL (inclusive) as outlined in Section 4.2.

          6. Vitamin B12: Above the lower limit of the reference range (may rescreen in 2 months).

          7. Folate: >/=2.0 ng/mL at Screening. May rescreen in a month.

          8. Ferritin: >/=40 ng/mL with the absence of microcytic or hypochromic RBCs.

          9. 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 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)>40 MIU/ml and estradiol <40 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 enrollment. For most types 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 approved contraceptive methods from the time of Screening
             until completion of the Follow-up Visit.

        Exclusion Criteria:

          1. Dialysis: Planning to initiate dialysis during the study or who have a high potential
             for initiating dialysis during study participation.

          2. Renal transplant: Renal transplant anticipated or scheduled within the study time
             period or subjects with a functioning renal transplant.

          3. Total CPK: >5x the upper limit of the reference range.

          4. HIV: Positive HIV antibody.

          5. History of myocardial infarction or acute coronary syndrome within the prior 6 months.

          6. History of stroke or TIAs.

          7. Heart failure: Class III/IV heart failure, as defined by the New York Heart
             Association (NYHA) functional classification system.

          8. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or
             lack of treatment, defined as DBP >100 mmHg or SBP>160 mmHg.

          9. 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) within the prior 6 months.

         10. 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).

         11. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis
             (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac
             disease).

         12. Hematological disease: Any hematological 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, hematological malignancy, myeloma,
             hemolytic anemia) or any other cause of anemia other than renal disease.

         13. 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, ALT or 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.

         14. Major surgery: Within the prior 12 weeks or planned during the study.

         15. Transfusion: Blood transfusion within the prior 12 weeks or an anticipated need for
             blood transfusion during the study.

         16. Ulcer and Active GI Bleeding: Evidence of active peptic, duodenal, or esophageal ulcer
             disease or active GI bleeding within the prior 12 weeks.

         17. 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).

         18. Malignancy: History of malignancy within 5 years of Screening 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.

         19. Hyperparathyroidism: Clinically significant hyperparathyroidism in the opinion of the
             Investigator, including subjects with parathyroid hormone (PTH) values ≥600 pg/mL.

         20. Eyes: History of proliferative retinopathy requiring treatment within the prior 12
             months, or macular edema requiring treatment.

         21. Severe reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product.

         22. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary
             supplements that are prohibited from Screening until the Follow-up Visit.

         23. Androgens: New androgen therapy or changes to pre-existing androgen regimen within
             prior 12 weeks.

         24. Prior investigational product exposure: The subject has participated in a clinical
             trial and has received an experimental investigational product within prior 30 days.

         25. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle
             and/or dietary restrictions outlined in the protocol.

         26. Other conditions: Any condition which in the investigators opinion should exclude the
             subject from participating in the study.

         27. Pregnancy and lactation: Pregnant females as determined by positive urine hCG test, OR
             women who are lactating at Screening or during the trial.