Phase III Study of GSK1278863 in Japanese Non-dialysis (ND) and Peritoneal Dialysis (PD) Subjects With Renal Anemia
Condition: Anaemia
MeSH terms: Anemia
Intervention: 1 to 4 mg tablets of GSK1278863; 6 mg GSK1278863 tablet; Epoetin beta pegol
Intervention description: 7.0 millimeters (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient, to be orally administered once daily.; 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of GSK1278863 as active ingredient, to be orally administered once daily.; An injectable formulation containing 25 micrograms µg, 50 µg, 75 µg, 100 µg, 150 µg, 200 µg, or 250 µg of epoetin beta pegol per syringe (0.3 mL), supplied as a glass syringe prefilled with epoetin beta pegol solution (clear colorless to pale yellow). Epoetin beta pegol will be subcutaneously administered once every 2 or 4 weeks.
Intervention MeSH terms: Glycine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 355.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Renal Anemia; Japanese; chronic kidney disease; Peritoneal dialysis; GSK1278863; Non-dialysis

Summary:

      This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to
      compare the efficacy and safety of GSK1278863 administered for 52 weeks versus epoetin beta
      pegol in approximately 286 Japanese ND and 50 PD subjects with renal anemia. The study will
      consist of three cohorts. Cohort 1 and Cohort 3 will consist of ND subjects
      (Erythropoiesis-Stimulating Agent [ESA] users and ESA non-users) randomized to receive
      GSK1278863 or epoetin beta pegol in a ratio of 1:1. PD subjects will be enrolled into Cohort
      2 and will receive GSK1278863. This study consists of a 4-week screening phase, a 52-week
      treatment phase (including primary efficacy evaluation period [Weeks 40 to 52]), and a 4-week
      follow-up phase following the treatment phase. The primary objective of this study is to
      demonstrate non-inferiority of GSK1278863 to epoetin beta pegol based on mean hemoglobin
      (Hgb) during the primary efficacy evaluation period in ND subjects. ESA non-users from Cohort
      1 will be excluded from the primary efficacy analysis. Study results will be used as pivotal
      study data for an NDA submitted for GSK1278863 for the treatment of renal anemia in Japan.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age (at the time of informed consent): >=20 years of age

          -  Screening verification only: Stage of chronic kidney disease (CKD) (ND subjects only):
             CKD stages 3, 4, and 5 defined by estimated glomerular filtration rate (eGFR) using
             the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI)
             formula

          -  Dialysis:

               -  Not on dialysis for at least 12 weeks prior to screening (ND subjects)

               -  On peritoneal dialysis (PD subjects)

          -  Use of ESA:

               -  ESA non-users: Have not used ESAs for 8 weeks prior to screening

               -  ESA users: Have used the same ESA for 8 weeks prior to screening. However, in the
                  ND subjects, the dose of darbepoetin alfa or epoetin beta pegol must be stable
                  (administered once every 4 weeks and up to one-step dose change during 8 weeks
                  prior to screening).

          -  Hgb: Determined at the site using an Hgb analyzer

               -  ESA non-users: >=8.0 g/dL and <11.0 g/dL

               -  ESA users: >=9.0 g/dL and <=13.0 g/dL

          -  Iron parameters: Ferritin >100 nanograms per milliliters (ng/mL) or transferrin
             saturation (TSAT) >20% (screening verification only)

          -  Gender (screening verification only): Female or male. Females: Not pregnant
             [demonstrated to be negative for human chorionic gonadotropin (hCG) in urine or
             serum], not breast-feeding, and meet at least one of the following:

               1. Females of non-childbearing potential are defined as follows:

                    -  Pre-menopausal with at least one of the following and no plans to utilize
                       assisted reproductive techniques (e.g., in vitro fertilization or donor
                       embryo transfer):

                    -  History of bilateral tubal ligation or salpingectomy

                    -  History of hysteroscopic tubal occlusion and postoperatively documented
                       bilateral tubal obstruction

                    -  History of hysterectomy

                    -  History of bilateral oophorectomy

                    -  Postmenopausal defined as: females 60 years of age or older or ; In females
                       <60 years of age, 12 months of spontaneous amenorrhea (in questionable cases
                       a blood sample with postmenopausal follicle stimulating hormone [FSH] and
                       estradiol concentrations is confirmatory [specified reference ranges]).
                       Females on hormone replacement therapy (HRT) whose menopausal status is in
                       doubt will be required to use one of the most effective 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.

               2. Females of childbearing potential must agree to comply with one of the
                  contraception methods listed as requirements in "GSK Listing of Most Effective
                  Contraceptive Methods for Females of Childbearing Potential" from 28 days prior
                  to the first dose of study medication until the completion of the follow-up visit
                  (for subjects randomized to the GSK1278863 group) or 7 weeks after the last dose
                  of study treatment (for subjects randomized to the Epoetin beta pegol group).

          -  Informed consent: Written informed consent, including adherence to the requirements
             and conditions specified in the consent form and the protocol, must be obtained from
             each subject as specified in Protocol.

        Exclusion Criteria:

        Chronic kidney disease (CKD)-related criteria

          -  Dialysis

               -  Cohort 1 and Cohort 3: Start or plan to initiate dialysis during the study

               -  Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study

          -  Kidney transplant: Planned living-related kidney transplant during the study
             Anemia-related criteria

          -  Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia

          -  Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or
             myelodysplastic syndromes

          -  Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or
             esophageal ulcer disease OR clinically significant GI bleeding within 8 weeks prior to
             screening or during a period from screening to Day 1.

        Cardiovascular disease-related criteria

          -  Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack:
             Diagnosed within 8 weeks prior to screening or during a period from screening to Day
             1.

          -  Heart failure: Class IV heart failure, as defined by the New York Heart Association
             (NYHA) functional classification system

          -  QT interval corrected for heart rate (QTc) (screening verification only): QTc >500
             milliseconds (msec) or QTc >530 msec in subjects with bundle branch block Note: QT
             interval corrected using the Bazett's formula (QTcB) will be used, and
             Electrocardiogram (ECG) can be mechanically or manually read.

        Other disease-related criteria

          -  Liver disease (if any of the following occurs):

               -  (Screening verification only) Alanine transaminase (ALT) >2 times upper limit of
                  normal (ULN)

               -  (Screening verification only) Bilirubin >1.5 times ULN (isolated bilirubin >1.5
                  times ULN is acceptable if bilirubin is fractionated and direct bilirubin is
                  <35%)

               -  Current unstable active liver or biliary disease (generally defined by the onset
                  of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric
                  varices, persistent jaundice, or cirrhosis) Note: Stable liver disease (including
                  asymptomatic gallstones, chronic hepatitis B/C, or Gilbert's syndrome) is
                  acceptable if the subject otherwise meets entry criteria..

          -  Malignancy: History of malignancy within 2 years prior to screening, or currently
             receiving treatment for cancer, (PD subjects only) complex renal cystic >3 centimeters
             (cm) (II F, III or IV based on the Bosniak classification) Note (ND subjects and PD
             subjects): The only exception is squamous cell or basal cell carcinoma of the skin
             that has been definitively treated >=8 weeks before screening.

          -  In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL)
             is medically risky.

        Concomitant medication and other study treatment-related criteria

          -  Iron: Planned use of intravenous iron during the screening phase or during a period
             from Day 1 to Week 4 Note: Oral iron is acceptable. However, the same dose regimen
             must be used throughout the screening phase and from Day 1 to Week 4.
             Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) are also
             acceptable only if used for at least 12 weeks prior to screening. However, they must
             be continued throughout the screening phase from Day 1 to Week 4.

          -  Severe allergic reactions: History of severe allergic or anaphylactic reactions or
             hypersensitivity to excipients in the investigational product or epoetin beta pegol

          -  Drugs and supplements: Use or planned use of any prescription or non-prescription
             drugs or dietary supplements that are prohibited during the study period (prohibited
             medications: strong inducers and inhibitor of Cytochrome P450 2C8 [CYP2C8])

          -  Prior investigational product exposure: Use of an investigational agent within 30 days
             or five half lives of the investigational agent (whichever is longer)

          -  Prior treatment with GSK1278863: Any prior treatment with GSK1278863 for a treatment
             duration of >30 days

        General health-related criteria

          -  Other conditions: Any other condition, clinical or laboratory abnormality, or
             examination finding that the investigator (or subinvestigator) considers would put the
             subject at unacceptable risk, which may affect study compliance or prevent
             understanding of the aims or investigational procedures or possible consequences of
             the study.