Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease

Study Overview
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Brief Summary
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This study aims to characterize the relationship between dose of GSK1278863 and hemoglobin (Hgb) response in hemodialysis-dependent (HDD) subjects with anemia associated with chronic kidney disease (CKD). 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. This study will consist of a screening phase of 3-9 weeks, a 4-week treatment phase and a follow-up visit approximately 4 weeks after completing treatment.

Official Title
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A 4-Week, Phase II, Randomized, Double-Blind, Dose-Ranging, Placebo-Controlled, Parallel-Group, Multi-Center Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease

Conditions
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Anaemia

Intervention / Treatment
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* Drug: GSK1278863
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age (Informed concent): Japanese >=20 years of age Gender (Screening 2 verification only): Female and male Females: must be of childbearing potential, and must agree to use one of the approved contraception methods from Screening 2 until completion of the Follow-up Visit. OR Of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrea [in questionable cases a blood sample with simultaneous follicle stimulating hormone 23.0 - 116.3 million international units (MIU)/millilitre (mL) and estradiol <= 10 picograms (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 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. Males: must agree to use one of the approved contraceptive methods from the time of Screening 2 until completion of the Follow-up Visit. Corrected QT interval (QTc) (Screening 2 verification only): Bazett's Correction of QT Interval (QTcB) <470 milliseconds (msec) or QTcB <480 msec in subjects with bundle branch block. There is no QTc inclusion criterion for a subject with a predominantly paced rhythm. Dialysis frequency: On hemodialysis (HD) three times weekly for at least 8 weeks prior to Screening 2 through Day 1. Dialysis adequacy (Screening 2 only): 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%. Hemoglobin: Target stable Hgb between 9.5-12.0 g/dL at screening. Stable erythropoiesis-stimulating agent (ESA) dose (Screening 2 only): Using the same ESA (epoetins or their biosimilar, or darbepoietin) with total weekly doses that varied by no more than 50% during the 4 weeks prior to Screening 2. Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous (IV) (<100 milligrams [mg]/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Screening 2, and Screening 2 through Week 4. Exclusion Criteria: Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period. Renal transplant: Renal transplant anticipated or scheduled within the study time period. High ESA dose (Screening 2 verification only): As defined by an epoetin dose of >=360 IU/kilograms (kg)/week IV or darbepoetin dose of >=1.8 micrograms (μg)/kg/week IV within the prior 8 weeks through Screening 2. methoxy polyethylene glycol epoetin beta (Screening 2 verification only): Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Screening 2. Vitamin B12: At or below the lower limit of the reference range Folate: <2.0 nanograms (ng)/mL (<4.5 nanomoles [nmol]/liters [L]) Iron status: Ferritine <100 ng/mL (<100 μg/L) AND Transferrin saturation (TSAT) <20% Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening 2 through Day 1. Stroke or transient ischemic attack: Within the 8 weeks prior to Screening 2 through Day 1. Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system or symptomatic right heart failure diagnosed prior to Screening 2 through Day 1. Hypertension: Defined using pre-dialysis vitals of diastolic blood pressure >100 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), except vascular access thrombosis, within the 8 weeks prior to Screening 2 through Day 1 Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months or macular edema requiring treatment.. Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Screening 2 through Day 1. 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 Screening 2 through Day 1. 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 (subinvestigator) would preclude the subject from participation in the study. Major surgery: Major surgery (excluding vascular access surgery) within the prior 8 weeks, within the Screening 2 to Day 1 or planned during the study. Transfusion: Blood transfusion within the prior 8 weeks, within the Screening 2 to Day 1 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 Screening 2 through Day 1. Acute infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within 8 weeks prior to Screening 2 through Day 1. 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 Screening 2 through Day 1. 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 Screening 2 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 Screening 2 through Day 1. Pregnancy or lactation: Pregnant females as determined by positive serum Human Chorionic Gonadotrophin (hCG) test (Screening 2 only) OR women who are lactating at Screening 2 and/or Day 1 or during the trial. Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator would consider inappropriate to participate in the study.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1278863 4 milligrams (mg)<br>Subjects will receive GSK1278863 4 mg once daily for 4 weeks | Drug: GSK1278863<br>* GSK1278863 will be supplied as film coated tablets for oral administration containing 1 mg, 2 mg, or 5 mg of GSK1278863.<br>|
| Experimental: GSK1278863 6 mg<br>Subjects will receive GSK1278863 6 mg once daily for 4 weeks | Drug: GSK1278863<br>* GSK1278863 will be supplied as film coated tablets for oral administration containing 1 mg, 2 mg, or 5 mg of GSK1278863.<br>|
| Experimental: GSK1278863 8 mg<br>Subjects will receive GSK1278863 8 mg once daily for 4 weeks | Drug: GSK1278863<br>* GSK1278863 will be supplied as film coated tablets for oral administration containing 1 mg, 2 mg, or 5 mg of GSK1278863.<br>|
| Experimental: GSK1278863 10 mg<br>Subjects will receive GSK1278863 10 mg once daily for 4 weeks | Drug: GSK1278863<br>* GSK1278863 will be supplied as film coated tablets for oral administration containing 1 mg, 2 mg, or 5 mg of GSK1278863.<br>|
| Placebo Comparator: Placebo<br>Subjects will receive placebo once daily for 4 weeks | Drug: Placebo<br>* Film coated tablets of GSK1278863 matching placebo for oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (CFB) in Hemaglobin (Hgb) at Week 4 | Baseline was defined as the value on Day 1. CFB was calculated by subtracting the baseline value from the post-dose value at Week 4. To model the dose-response relationship a four-parameter Emax model was used. E0 is the expected Hgb change from Baseline for a participant receiving placebo and experiencing the average Hgb Baseline observed in the study. Emax is the expected Hgb change from Baseline for a participant receiving the highest dose above which no further increase in response can be achieved. ED50 is the dose that attains the intermediate response. Gamma is the slope parameter. Minimal Effective Dose (MED) is defined as the smallest dose that achieves a placebo-corrected change of 0.5 g/dL over Week 4. Target dose (TD) is defined as the dose that achieves a placebo-corrected 1.0 g/dL change over Week 4. Maximum Acceptable Dose (MAD) is defined as the dose that achieves a placebo-corrected 2.0 g/dL change over Week 4. | Baseline (Day 1) and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CFB in Hgb Upto Week 8 | Hgb assessments were performed at Baseline, Week 1, Week 2, Week 3, W eek4/Early withdrawal and Week 8 (follow-up) based on central laboratory (Quest diagnosis). Baseline was defined as the value on Day 1. CFB was calculated by subtracting the Baseline value from the post-dose value at Week 4. | Baseline (Day 1) Upto Week 8 | 
| Number of Participants Who Achieved Hgb Response at Week 4 | Hgb response was defined as achieving an increase of at least 0.5 g/dL, 1.0 g/dL, 1.5 g/dL, and 2.0 g/dL in Hgb. The number of participants with Hgb response: Hgb increase <-1.0, Hgb increase -1.0 -< -0.5, Hgb increase -0.5 -< 0.5, Hgb increase 0.5 -< 1.0 and Hgb increase >=1.0 have been presented. | Week 4 | 
| Percentage of Participants Who Achieved Hgb Response at Week 4 | Hgb response was defined as achieving an increase of at least 0.5 g/dL, 1.0 g/dL, 1.5 g/dL, and 2.0 g/dL in Hgb. The percentage of participants with Hgb response: Hgb increase <-1.0, Hgb increase -1.0 -< -0.5, Hgb increase -0.5 -< 0.5, Hgb increase 0.5 -< 1.0 and Hgb increase >=1.0 have been presented. | Week 4 | 
| Number of Participants Who Reached Pre-defined Hgb Stopping Criteria | Hgb stopping criteria was defined as: (1) Hgb <7.5 g/dL (2) 7.5 <= Hgb <1 3.0 g/dL and >2 g/dL Hgb change over 2W (3) Hgb >=13.0 g/dL. The number of participants who reached pre-defined Hgb stopping criteria have been presented. | Upto Week 4 | 
| Maximum Observed CFB in Erythropoietin (EPO) Upto Week 4 | Blood samples for EPO were collected on Day 1 (pre-dose), Week 2 (collected approx 6-12 hours post-dose on arrival and after 1, 2 and 3 hours) and Week 4 (pre-dose and 3 hours post-dose). Maximum observed value meant maximum value between Week 1 and Week 4. Baseline was defined as the value on Day 1. Maximum observed CFB was calculated by subtracting the Baseline value from the maximum observed value between Week 1 and Week 4. | Baseline (Day 1) Upto Week 4 | 
| Maximum Observed Percent CFB in Peak Vascular Endothelial Growth Factor (VEGF) Upto Week 4 | Blood samples for VEGF were collected on Day 1 (pre-dose), Week 2 (collected approximately 6-12 hours post-dose on arrival and after 1, 2 and 3 hours) and Week 4 (pre-dose and 3 hours post-dose). Maximum observed value meant maximum value between Week 1 and Week 4. Baseline was defined as the value on Day 1. Maximum observed percent CFB was calculated as 100 multiplied by the maximum observed exponential mean change on a log scale minus 1. | Baseline (Day 1) Upto Week 4 | 
| Percent CFB in Hepcidine Upto Week 4 | Blood samples for hepcidine were collected on Day 1 (pre-dose), Week 2 (collected approximately 6-12 hours post-dose) and Week 4 (pre-dose). Baseline was defined as the value on Day 1. Percent CFB was calculated as 100 multiplied by the exponential mean change on a log scale minus 1. | Baseline (Day 1) Upto Week 4 | 
| CFB in Ferritin at Week 4 | Ferritin was used as marker of iron metabolism and utilization. Baseline was defined as the value on Day 1. CFB was calculated by subtracting the Baseline value from the post dose value at Week 4. | Baseline (Day 1) and Week 4 | 
| CFB in Total Iron Binding Capacity [TIBC], Unbound Iron Binding Capacity [UIBC] and Iron at Week 4 | TIBC, UIBC and Iron were used as marker of iron metabolism and utilization. Baseline was defined as the value on Day 1. CFB was calculated by subtracting the Baseline value from the post-dose value at Week 4. | Baseline (Day 1) and Week 4 | 
| CFB in Transferrin at Week 4 | Transferrin was used as marker of iron metabolism and utilization. Baseline was defined as the value on Day 1. CFB was calculated by subtracting the Baseline value from the post-dose value at Week 4. | Baseline (Day 1) and Week 4 | 
| Percent CFB in Transferrin Saturation (TS) at Week 4 | TS was used as marker of iron metabolism and utilization. Baseline was defined as the value on Day 1. Percent CFB was calculated as 100 multiplied by the exponential mean change on a log scale minus 1. | Baseline (Day 1) and Week 4 | 
| Plasma Pharmacokinetic Concentration of GSK1278863 and Metabolites (M) at Week 4 | Blood samples for plasma pharmacokinetic analysis were collected at Week 4 (pre-dose, 1, 2, 3 hours post-dose). Individual plasma GSK1278863 and M-GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531401, GSK2531403 concentrations have been presented. | Week 4 | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) on Therapy | An AE is defined as any untoward medical occurrence in clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any AE which results in death; is life-threatening; requires participant hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. | Upto Week 4 | 
| Number of Participants With Chemistry and Hematology Data of Potential Clinical Importance (PCI) Upto Week 4 | The PCI range was as follows: alkaline phosphates >= 3 times upper limit of normal range [ULRR]), potassium (>0.5 millimoles/liter below the LLRR or >1.0 millimoles/liter above the ULRR), phosphate (>0.323 millimoles/liter above ULRR or below lower limit reference range [LLRR]), glucose (<3.9 or >22 millimoles/liter), magnesium (<LLRR or > 0.3 milimoles/liter above ULRR), lymphocytes <0.5x LLRR, neutrophils (<0.5 times LLRR), platelets (80 or >500 times giga/liter), platelets (80 or >500 times giga/liter) and leukocytes >1 x giga/liter below the LLRR or >5 x GI/L above the ULRR. The participants who had PCI values higher and lower than the reference range have been presented. | Upto Week 4 | 
| Number of Participants With Vital Signs Parameters Systolic and Diastolic Blood Pressure (SBP,DBP) of PCI Upto Week 4 | Vital signs SBP and DBP were recorded pre-dialysis and post-dialysis. Measurements were taken from the participant while in a seated position or semi-supine in the dialysis chair. PCI range for SBP was < 85 or > 170 and for DBP was < 45 or > 100 millimeters of mercury. Participant's with values high and low from the PCI range have been presented. | Upto Week 4 | 
| Number of Participants With Vital Sign Parameter Heart Rate (HR) of PCI Upto Week 4 | Vital sign HR was recorded pre-dialysis and post-dialysis. Measurements were taken from the participant while in a seated position or semi-supine in the dialysis chair. PCI range for HR was < 40 or > 110 beats per minute. Participant's with values higher than the PCI range have been presented. | Upto Week 4 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings Upto Week 4 | Full 12-lead ECGs included heart rate, PR, QRS, QT and QTc intervals. Measurements were taken from the participant while in a supine position. ECGs were performed consistently either before or after dialysis throughout the study. ECG abnormalities characterized as abnormal-not clinically significant (A-NCS) and abnormal-clinically significant (A-CS) upto W4 have been presented. | Upto Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemodialysis, GSK1278863, Pharmacokinetics, Erythropoiesis Stimulating Agents, Chronic Kidney Disease, Hemoglobin, Recombinant Erythropoietin, Prolyl Hydroxylase Inhibitor, Anemia