Trial Outcomes & Findings for Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis (NCT NCT02243306)

This repeat-dose, pharmacokinetic (PK) study of GSK1278863 was conducted at two centers in the United States (US). Participants with End Stage Renal Disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) were included in this study.

A total of 20 participants with ESRD were screened; of which 12 were screen failures and 8 entered the study to receive 5 milligrams (mg) of GSK1278863 once daily for 14 days.

Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis

Serial blood samples were collected from participants at indicated time points for Pharmacokinetic (PK) analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. PK Population comprised of participants in the 'All Subjects' Population for whom a PK sample was obtained and analyzed.

Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2487818 and GSK2531398). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants.

Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/birth defect, other situations, and is associated with liver injury and impaired liver function. Analysis was performed on All Subjects Population which comprised of all enrolled participants who received at least one dose of study treatment.

Blood samples were collected from participants to evaluate clinical chemistry parameters including glucose, calcium, chloride, CO2, potassium, sodium and urea. Change from Baseline in clinical chemistry parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical chemistry parameters including albumin and protein. Change from Baseline in clinical chemistry parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical chemistry parameters including direct bilirubin, bilirubin, creatinine and urate. Change from Baseline in clinical chemistry parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical chemistry parameters including ALP, AST and GGT. Change from Baseline in clinical chemistry parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical chemistry parameters including ALT and creatinine kinase. Change from Baseline in clinical chemistry parameters at Day 3, Day 7, Day 11, Day 14 and Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants to evaluate clinical hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. NA indicates data is not available. Mean and standard deviation are presented. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical hematology parameters including erythrocyte and reticulocyte. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. NA indicates data is not available. Mean and standard deviation are presented. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical hematology parameters including hematocrit. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical hematology parameters including hemoglobin. Change from Baseline in clinical hematology parameters at Day 3, Day 7, Day 11 and Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants to evaluate clinical hematology parameters including MCHC. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical hematology parameters including MCV. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Blood samples were collected from participants to evaluate clinical hematology parameters including MCH. Change from Baseline in clinical hematology parameters at Day 17 are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only participants with data available at the specified time point were analyzed.

Single measurements of 12-lead ECG were obtained in supine position after at least 10 minutes of rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. Participants with abnormal ECG findings at worst-case observation Carried Forward for triplicate measurements (WOCF) post-Baseline visit are presented. Only participants with data available at WOCF visit were analyzed.

Vital sign measurements including SBP and DBP were taken in a supine position after at least 5 minutes of rest. Change from Baseline in SBP and DBP at Day 17 and Day 24 (follow-up) are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Vital sign measurements including pulse rate were taken in a supine position after at least 5 minutes of rest. Change from Baseline in pulse rate at Day 17 and Day 24 (follow-up) are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Vital sign measurements including body temperature were taken in a supine position after at least 5 minutes of rest. Change from Baseline in body temperature at Day 17 and Day 24 (follow-up) are presented. Day-1 was considered as Baseline value. Change from Baseline was calculated as post-randomization values minus Baseline value. Mean and standard deviation are presented. NA indicates data is not available. Standard deviation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

A complete physical examination was planned to include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. This analysis was planned but not performed. Any significant finding was captured as an AE.

Peritoneal dialysate samples for PK analysis of GSK1278863 and metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401) were collected. Peritoneal dialysis clearance of GSK1278863 and metabolites was calculated from Day 14 dialysate excretion data as total amount of analyte excreted over 24 hours divided by plasma AUC (0-tau). Geometric mean and geometric coefficient of variation are presented. NA indicates data is not available. Geometric coefficient of variation could not be calculated due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403, GSK2531401). Geometric mean and geometric coefficient of variation have been presented for all metabolites. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants, which is indicated by NA. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Median and full range have been presented for all metabolites. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The observed accumulation ratio was determined to estimate the extent of accumulation for GSK1278863 and metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401) after repeat dosing. Accumulation ratio was calculated by using AUC (0-tau) values at Day 1 and Day 14. Analysis was performed using mixed effect model fitted with day (single and repeat dose) as fixed effect and participant as random effect. Mean ratio and 90% confidence intervals have been presented.

Time invariance ratio for GSK1278863 and metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401) was calculated by analyzing AUC (0-inf) at Day 1 and AUC (0-tau) at Day 14. Analysis was performed using mixed effect model fitted with day (single and repeat dose) as fixed effect and participant as random effect. Mean ratio and 90% confidence intervals have been presented. NA indicates data is not available. Data could not be calculated due to insufficient data.

Serial blood samples were collected from participants at indicated time points to analyze plasma concentration of erythropoietin after repeat-dose administration of GSK1278863. Geometric mean and geometric coefficient of variation have been presented. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Serial blood samples were collected from participants at indicated time points to analyze plasma concentration of hepcidin after repeat-dose administration of GSK1278863. Geometric mean and geometric coefficient of variation have been presented. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).