Trial Outcomes & Findings for Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease (NCT NCT02019719)

This was a study to evaluate dose-response of GSK1278863 in approximately 95 Japanese Hemodialysis-dependent (HDD) participants with anemia associated with Chronic Kidney Disease (CKD) conducted across 21 centers in Japan from 05 November 2013 to 06 August 2014.

This study consisted of a screening phase of 3-9 Week , a 4 Week treatment phase and a follow-up visit that occurred approximately 4 Week after completing treatment. Study completion was defined as completing the final visit including those in the follow-up period.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.